Compounds for the treatment of neuromuscular disorders

ABSTRACT

The present invention relates to compounds suitable for treating, ameliorating and/or preventing neuromuscular disorders, including the reversal of drug-induced neuromuscular blockade. The compounds as defined herein preferably inhibit the CIC-1 ion channel.

CROSS REFERENCE TO RELATED APPLICATION

This application is a Continuation-In-Part of application Ser. No.15/842,807, filed Dec. 14, 2017, the contents of which is herebyexpressly incorporated by reference in its entirety for all purposes.

FIELD OF INVENTION

The present invention relates to compounds for use in treating,ameliorating and/or preventing neuromuscular disorders, including thereversal of drug-induced neuromuscular blockade. The compounds asdefined herein preferably inhibit the CIC-1 ion channel. The inventionfurther relates to methods of treating, preventing and/or amelioratingneuromuscular disorders, by administering said composition to a personin need thereof.

BACKGROUND

Walking, breathing, and eye movement are examples of essential everydayphysiological activities that are powered by contractile activity ofskeletal muscle. Skeletal muscles are inherently resting and contractileactivity exclusively occurs in response to commands from the centralnervous system. Such neuronal commands take the form of actionpotentials that travel from the brain to the muscle fibers in severalsteps. The neuromuscular junction (NMJ) is the highly specializedmembrane area on muscle fibers where motor neurons come into closecontact with the muscle fibers, and it is at NMJ that neuronal actionpotentials are transmitted to muscular action potentials in a one-to-onefashion via synaptic transmission.

Neuromuscular transmission refers to the sequence of cellular events atthe NMJ whereby an action potential in the lower motor neuron istransmitted to a corresponding action potential in a muscle fiber. Whena neuronal action potential arrives at the pre-synaptic terminal ittriggers influx of Ca²⁺ through voltage gated P/Q-type Ca²⁺ channels inthe nerve terminal membrane. This influx causes a rise in cytosolic Ca²⁺in the nerve terminal that triggers exocytosis of acetylcholine (ACh).Released ACh next diffuses across the synaptic cleft to activatenicotinic ACh receptors in the post-synaptic, muscle fiber membrane.Upon activation, ACh receptors convey an excitatory current flow of Na⁺into the muscle fiber, which results in a local depolarization of themuscle fiber at the NMJ that is known as the endplate potential (EPP).If the EPP is sufficiently large, voltage gated Na⁺ channels in themuscle fiber will activate and an action potential in the muscle fiberwill ensue. This action potential then propagates from NMJ throughoutthe muscle fiber and triggers the Ca²⁺ release from the sarcoplasmicreticulum. The released Ca²⁺ activates the contractile proteins withinthe muscle fibers thus resulting in contraction of the fiber.

Failure in the neuromuscular transmission can arise from bothpre-synaptic dysfunction (Lambert Eaton syndrome, amyotrophic lateralsclerosis, spinal muscular atrophy) and as a result of post-synapticdysfunction as occurs in myasthenia gravis. Failure to excite and/orpropagate action potentials in muscle can also arise from reduced muscleexcitability such as in critical illness myopathy (CIM). In LambertEaton syndrome, an autoimmune attack against the pre-synaptic P/Q-typeCa²⁺ channels results in markedly reduced Ca²⁺ influx into the nerveterminal during the pre-synaptic action potential and, consequently, areduced release of ACh into the synaptic cleft. In myasthenia gravis themost common finding is an autoimmune attack on the post-synapticmembrane either against the nicotinic ACh receptors or the musk-receptorin the muscle fiber membrane. Congenital forms of myasthenia are alsoknown. Common to disorders with neuromuscular transmission failure(Lambert Eaton syndrome, amyotrophic lateral sclerosis, spinal muscularatrophy and myasthenia gravis) is that the current flow generated by AChreceptor activation is markedly reduced, and EPPs therefore becomeinsufficient to trigger muscle fiber action potentials. Neuromuscularblocking agents also reduce EPP by antagonizing ACh receptors. In CIMwith reduced muscle excitability, the EPP may be of normal amplitude butthey are still insufficient to trigger muscle fiber action potentialsbecause the membrane potential threshold for action potential excitationhas become more depolarized because of loss-of-function of voltage gatedNa⁺ channels in the muscle fibers.

While ACh release (Lambert Eaton, amyotrophic lateral sclerosis, spinalmuscular atrophy), ACh receptor function (myasthenia gravis,neuromuscular blockade) and function of voltage gated Na⁺ channels (CIM)are essential components in the synaptic transmission at NMJ, themagnitude of the EPP is also affected by inhibitory currents flowing inthe NMJ region of muscle fibers. These currents tend to outbalanceexcitatory current through ACh receptors and, expectedly, they therebytend to reduce EPP amplitude. The most important ion channel forcarrying such inhibitory membrane currents in muscle fibers is themuscle-specific CIC-1 Cl⁻ ion channel.

ACh esterase (AChE) inhibitors are traditionally used in the treatmentof myasthenia gravis. This treatment leads to improvement in mostpatients but it is associated with side effects, some of which areserious. Because ACh is an import neurotransmitter in the autonomicnervous system, delaying it's breakdown can lead to gastric discomfort,diarrhea, salivation and muscle cramping. Overdosing is a seriousconcern as it can lead to muscle paralysis and respiratory failure, asituation commonly referred to as cholinergic crisis. Despite theserious side effects of AChE inhibitors, these drugs are today thetreatment of choice for a number of disorders involving neuromuscularimpairment. In patients where pyridostigmine (a parasympathomimetic anda reversible ACHE inhibitor) is insufficient, corticosteroid treatment(prednisone) and immunosuppressive treatment (azathioprine) is used.Plasma exchange can be used to obtain a fast but transient improvement.

Unfortunately, all of the currently employed myasthenia gravis drugregimens are associated with deleterious long-term consequences. Inaddition, the otherwise safe use of common drugs such asanti-infectives, cardiovascular drugs, anticholinergics,anticonvulsants, antirheumatics and others have been reported to worsenthe symptoms of myasthenia gravis patients.

The CIC-1 ion channel is emerging as a target for potential drugs,although its potential has been largely unrealized.

SUMMARY

The present inventors have identified a group of compounds thatalleviate neuromuscular junction disorders through inhibition of CIC-1channels.

Thus, for the first time, it has been found that compounds that inhibitthe CIC-1 ion channels are capable of restoring neuromusculartransmission, as evidenced by the data generated by investigation of thecompound set in biological models described herein. These compounds thusconstitute a new group of drugs that can be used to treat or amelioratemuscle weakness and muscle fatigue in neuromuscular junction disorderscaused by disease or by neuromuscular blocking agents.

The present invention thus concerns the use of CIC-1 ion channelinhibitors in the treatment of a range of conditions, such as reversalof block, ALS and myasthenic conditions, in which muscle activation bythe nervous system is compromised and symptoms of weakness and fatigueare prominent.

In one aspect the invention concerns a composition comprising a compoundof Formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   m is 0, 1, 2, 3, 4 or 5;        -   Y is selected from the group consisting of O, NH, N—CHs,            CH₂, CH₂—O, S and SO₂;        -   X₁, X₂ and X₃ are independently selected from the group            consisting of CH and N;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a C₃₋₆-cycloalk(en)yl or a            halo-C₃₋₆-cycloalk(en)yl;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R⁵ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃, nitro and halo; or R₁ and            R₂ are linked to form a ring;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl;        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl;            for use in treating, ameliorating and/or preventing a            neuromuscular disorder, and/or for use in reversing and/or            ameliorating a neuromuscular blockade after surgery.

In one aspect the invention concerns a method of treating, preventingand/or ameliorating a neuromuscular disorder, said method comprisingadministering a therapeutically effective amount of the composition asdefined herein to a person in need thereof.

In one aspect the invention concerns use of a composition as definedherein, for the manufacture of a medicament for the treatment,prevention and/or amelioration of a neuromuscular disorder, and/or forreversing and/or amelioration of a neuromuscular blockade after surgery.

In one aspect the invention concerns a method of reversing and/orameliorating a neuromuscular blockade after surgery, said methodcomprising administering a therapeutically effective amount of thecomposition as defined herein to a person in need thereof.

In one aspect the invention concerns a method for recovery ofneuromuscular transmission, said method comprising administering atherapeutically effective amount of the composition as defined herein toa person in need thereof.

In one aspect the invention concerns a composition as defined herein foruse in recovery of neuromuscular transmission.

In one aspect, the invention concerns a compound of Formula (I.2):

-   -   wherein:        -   R¹ is selected from the group consisting of hydrogen, F, Cl,            Br, I, —CN, —CF₃, Cl₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,            C₄ cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;        -   for use in treating, ameliorating and/or preventing a            neuromuscular disorder, and/or for use in reversing and/or            ameliorating a neuromuscular blockade,        -   with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In another aspect, the invention concerns a compound of Formula (II.2):

-   -   wherein:        -   R¹ is selected from the group consisting of hydrogen, F, Cl,            Br, I, —CN, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;        -   with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In one aspect, the invention concerns a compound of Formula (IIa):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, Cl₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅            alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl,            each of which may be optionally substituted with one or            more, identical or different, substituents R⁵;        -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl            optionally substituted with one or more, identical or            different, substituents R⁷, C₃₋₆ cycloalkyl optionally            substituted with one or more, identical or different,            substituents R⁷, phenyl optionally substituted with one or            more, identical or different, substituents R⁸ and benzyl            optionally substituted with one or more, identical or            different, substituents R⁸;        -   R⁵ is independently selected from the group consisting of            deuterium, F, OC₁₋₅ alkyl optionally substituted with one or            more, identical or different, substituents R⁷, OC₃₋₅            cycloalkyl optionally substituted with one or more,            identical or different, substituents R⁷, and OH;        -   R⁶ is independently selected from the group consisting of            hydrogen and deuterium;        -   R⁷ is independently selected from the group consisting of            deuterium and F;        -   R⁸ is independently selected from the group consisting of            deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and        -   n is an integer 0, 1, 2, 3 or 4;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;            with the proviso that:    -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1 or        2, then R³ is not methyl;    -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1,        then R³ is not ethyl;    -   when R¹ is Cl, R⁴ is H or Me or 4-methoxyphenyl or        4-nitrophenyl, R⁵ is H, R⁶ is H and n is 0, then R³ is not        methyl;    -   when R¹ is Br, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is        not methyl or isopropyl;    -   when R¹ is Br, R⁴ is Me, R⁵ is H, R⁶ is H and n is 0, then R³ is        not isopropyl; and        when R¹ is I, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is        not methyl.

In yet another aspect, the invention concerns a composition comprising acompound as defined herein.

In one aspect the invention concerns use of a composition as definedherein for the manufacture of a medicament for the recovery ofneuromuscular transmission. In another aspect, the invention concerns acomposition comprising a compound as defined herein and uses thereof,such as in treating, ameliorating and/or preventing a neuromusculardisorder, and/or for use in reversing and/or ameliorating aneuromuscular blockade.

DESCRIPTION OF DRAWINGS

FIGS. 1A-1C: Experimental methods for compromising neuromusculartransmission and the approaches employed to selectively activatecontractions either via stimulation of the motor nerve or by directlyexciting the rat muscle fibers. Soleus muscles were stimulated tocontract using three different methods: In FIG. 1A, the muscle wasstimulated to contract either directly using field stimulation withpulses of 0.2 ms duration or indirectly through stimulation of the nerveusing a suction electrode. In FIG. 1B and FIG. 10 , muscles werestimulated directly as described above or indirectly via the nerve usingfield stimulation with short pulses of 0.02 ms. Two different methods ofcompromising neuromuscular transmission were applied: In FIG. 1A andFIG. 1B, a sub-maximal concentration of tubocurarine (0.2 μM) was usedto inhibit ACh receptors in the post-synaptic muscle fiber membrane. InFIG. 10 , neuromuscular transmission was reduced by elevatingextracellular Mg²⁺ to 3.5 mM. In experiments were nerve-stimulation wasconducted using a suction electrode, the electrical activity of themuscle could be recorded as M-waves (Inserts in FIG. 1A). The entireM-wave train is shown with the first and the last M-waves in the trainsenlarged above.

FIGS. 2A-2B. Effect of CIC-1 channel inhibition with 9-AC onnerve-stimulated force in rat soleus muscles exposed to tubocurarine orelevated extracellular Mg²⁺. Muscles were stimulated to contract byactivation of the motor nerve using a suction electrode. Duringexperiments, the muscles contracted every 10 min for 2 s in response to60 Hz stimulation. FIG. 2A shows representative recordings of tetanifrom a soleus muscle from a 4-week-old animal that first contracted incontrol conditions, then during the pre-incubation with tubocurarineand, finally, in the presence of both tubocurarine and 9-AC. At the endof the experiment, tubocurarine was washed out to ensure full recoveryof contractile force. M-wave recordings from the muscle have beenincluded for the force responses indicated by i, ii and iii. The entireM-wave train is shown with the first and the last M-waves in the trainsenlarged above. To depress any myotonia with the pronounced CIC-1channel inhibition with 9-AC, 10 nM TTX was added together withtubocurarine. FIG. 2B shows representative recordings of tetani from asoleus muscle from a 4-week-old animal that first contracted in controlconditions, then during the pre-incubation with 3.5 mM Mg²⁺ and,finally, at 3.5 mM Mg²⁺ in the presence of 9-AC. When returned to normalextracellular Mg²⁺ of 1.2 mM, full contractile force ensued. M-waverecordings from the muscle have been included for the force responsesindicated by i, ii and iii as described in A.

FIGS. 3A-3B. Example of recovery of nerve-stimulated force with aclofibric acid derivative, C8, in muscles exposed to 150 nMtubocurarine. The motor nerve was stimulated every 10 min for 2 s with30 Hz with field stimulation using short duration pulses. FIG. 3A showsforce recordings from two muscles with the traces being overlaid toillustrate the effect of C8 clearly. Traces are shown before additiontubocurarine, after 40 min with tubocurarine, and after 110 mintubocurarine. After 40 min with tubocurarine, 50 μM C8 was added to themuscle that is presented by black traces. FIG. 3B shows averageobservations from 5 muscles treated with C8 and 5 control musclesexposed to only tubocurarine. Dotted lines indicate the recovery ofnerve-stimulated force in the muscles treated with C8 compared to theirforce production after 40 min with tubocurarine. This recovery of forcewas used in Table 1.

FIGS. 4A-4C. A three-electrode technique was used to determine theeffect of clofibric acid derivatives on the resting membraneconductance, G_(m). Three electrodes were inserted into the same musclefiber enabling recordings of the membrane potential response to theinjection of square current pulses at three inter-electrode distances(dist1<dist2<dist3). FIG. 4A shows the voltage responses at threeinter-electrode distances in a control muscle fiber, and in a fiberexposed to 10 μM C8. FIG. 4B to determine G_(m) the steady statedeflection of the membrane potential was measured at each of the threeinter-electrode distances. The magnitude of these steady statedeflections were next plotted against the inter-electrode distance, andthe data was fitted to a two-parameter exponential function (lines).From these parameters the fiber length constant and input resistancewere obtained enabling G_(m) to be calculated. FIG. 4C shows G_(m) at arange of C8 concentrations. By fitting a sigmoidal function to this datathe concentration of C8 that reduced G_(m) by 50% was obtained and thishas been presented in Table 3.

FIGS. 5A-5E. Effect of C8 and neostigmine on the tubocurarineconcentration required to reduce nerve-stimulated force in soleusmuscles. Muscles from 4-week-old rats were stimulated to contract byactivating the motor nerve with short duration pulses in fieldstimulation. Muscles contracted every 10 min for 2 s in response to 30Hz stimulation. Four different experimental conditions were used. Thus,muscles were initially incubated for 30 min in either i) controlconditions, ii) with 50 μM C8, iii) in the presence of 10 nMneostigmine, or iv) with the combination of neostigmine and C8. Afterthis pre-incubation, increasing concentrations of tubocurarine wereadded to the bath solutions with 60 min (corresponding to sixcontractions) between each increase in tubocurarine. FIG. 5A showsrepresentative recordings of force at different concentrations oftubocurarine in a control muscle. FIG. 5B similar to FIG. 5A but thismuscle had been pre-incubated with C8. FIG. 5C similar to FIG. 5A butthis muscle had been pre-incubated with neostigmine. FIG. 5D similar toFIG. 5A but this muscle had been pre-incubated with the combination ofC8 and neostigmine. The force integral (AUC) was determined at eachtubocurarine concentration. Such AUC determinations were plotted againsttubocurarine concentration for each muscle. FIG. 5E shows such plots ofAUC for muscles in FIG. 5A-FIG. 5D. The lines connecting the symbols arefits of the data to a sigmoidal function from which the tubocurarineconcentration that was required to reduce AUC to 50% could be obtained(Tuba)). The averages of Tuba) in the four groups of muscles are givenin Table 4.

FIGS. 6A-6E. Effect of a C8 and 3,4-AP on the extracellular Mg²⁺concentration required to reduce nerve-stimulated force in soleusmuscles. Muscles from 4-week-old rats were stimulated to contract byactivating the motor nerve with short duration pulses in fieldstimulation. Muscles contracted every 10 min for 2 s in response to 30Hz stimulation. Four different experimental conditions were used. Thus,muscles were initially incubated for 30 min in either i) controlconditions, ii) with 50 μM C8, iii) in the presence of 10 μM 3,4-AP, oriv) with the combination of 3,4-AP and C8. After this pre-incubation,the extracellular Mg²⁺ was progressively increased in the bath solutionsevery 60 min resulting in six contractions between each increase inextracellular Mg²⁺. FIG. 6A shows representative recordings of force atdifferent concentrations of Mg²⁺ in a control muscle. FIG. 6B similar toFIG. 6A but this muscle had been pre-incubated with C8. C) similar to A)but this muscle had been pre-incubated with 3,4-AP. FIG. 6B similar toFIG. 6A but this muscle had been pre-incubated with the combination ofC₈ and 3,4-AP. The force integral (AUC) was determined at eachextracellular Mg²⁺ concentration. AUC was plotted against Mg²⁺concentration and the data was fitted to a sigmoidal function. Thisprovided the extracellular Mg²⁺ concentration that was required toreduce the nerve-stimulated force to 50% (Mg₅₀) under the four differentconditions (see Table 5).

FIGS. 7A-7B. Effects of C8 on EPP amplitude in rat soleus muscle.Intracellular electrodes were inserted near visible nerve branches inthe muscle. The solution contained 1 μM μ-conotoxin GiiiB to blockNaV1.4. Under these conditions nerve-stimulation only resulted in EPPformation in the fibers and it did not trigger muscle fiber actionpotentials. FIG. 7A shows representative EPPs under control conditionsand with two concentrations of C8. FIG. 7B shows average EPP amplitudesin the fibers. *Indicates significantly different from control asevaluated using a student t-test.

FIGS. 8A-8B. Effects of C8 on contractile force in human musclesdepressed by elevated extracellular K⁺ and low dose of TTX. FIG. 8Ashows effect of adding 150 μM C8 on force in a muscle at elevated K⁺ andwith TTX. FIG. 8B shows the average force at elevated K⁺ in the presenceor absence of C8. *Indicates significant different as evaluated using aone-tailed student t-test.

FIGS. 9A-9B. Effects of I.P. C8 injection (20 mg/kg) on runningperformance of rats after I.P. injection of tubocurarine (0.13 mg/kg).FIG. 9A illustrates the design of the experiments. Prior to Day One theanimals had been familiarized to the rotarod in three training sessionsdistributed over two days. FIG. 9B shows the distance covered by therats on the two days 21-26 mins after injection of tubocurarine. FIG. 9Cshows the increase in performance on Day Two when compared toperformance on Day One. FIG. 9D shows the number of animals that on DayTwo had an increased performance of more than 100% compared toperformance on Day One.

FIG. 10 . Effects of C8 on running performance after inducing passivemyasthenia gravis in rats using MAB35 monoclonal antibody. Prior to I.P.injection of MAB35 the animals had been familiarized to the rotarod overthree training sessions distributed over two days. After I.P. injectionof MAB35 the running performance of the animals was monitored regularlyand if a stable reduction in performance developed, the animals weregiven either sham, 20 mg/kg C8 or 30 mg/kg C8. After this treatmentperformance was monitored every second hour. *Indicates significantdifferent as evaluated using student t-test.

FIGS. 11A-11C. FIG. 11A shows a schematic representation of thepositioning of the three microelectrodes (V₁, V₂ and V₃) when insertedin a single skeletal muscle fibre for G_(m) determination. Please notethat the drawing illustrates only the impaled fibre although it is partof an intact muscle that contains many such fibres. All electrodesrecorded the membrane potential of the fibre and the two peripheralelectrodes were used to inject current (−30 nA, 50 ms). The electrodeswere inserted with known inter-electrode distances (X₁, X₂ and X₃).After insertion, current was passed first via the V₁ electrode and thenvia the V₃ electrode. The resulting deflections in the membrane voltagewere measured by the other electrodes. The steady state deflections inmembrane potential were measured and divided by the magnitude of theinjected current (−30 nA) to obtain transfer resistances. These werenext plotted against inter-electrode distances, and fitted to anexponential function (FIG. 11B), from which G_(m) could be calculatedusing linear cable theory. The approach described in FIGS. 11A and 11B,was repeated for several muscle fibres in the muscle during exposure atincreasing concentrations of compound A-19, with approx. 10 fibres ateach concentration. Average G_(m) at each concentration was plotted as afunction of compound concentration in FIG. 11C, and fitted to a4-parameter sigmoidal function from which the EC₅₀ value for thecompound was obtained (dashed line)

FIGS. 12A-12B. FIG. 12A shows representative force traces before andafter exposure to compound A-19. Force traces from a representativemuscle stimulated to contract in 1) control condition before addition ofneuromuscular blocking agent, 2) the force response to stimulation after90 minutes incubation with Tubocurarine. Here the muscle displays severeneuromuscular transmission impediment, and 3) The muscle force responseafter addition of 50 μM compound A-19. FIG. 12B shows average force(AUC) from 3 muscles relative to their initial force. The tracespresented in FIG. 12A (1, 2, 3), correspond to the dotted lines in FIG.12B, respectively. Thus, force is lost due to 90 min incubation intubocurarine and is subsequently recovered when compound A-19 is added.

FIG. 13A-13B: FIG. 13A illustrates the voltage protocol used to evokecurrents in whole cell patches of CHO cells expressing human CIC-1channels. FIG. 13B shows representative whole cell current traces from apatched CHO cell expressing human CIC-1 channels. Currents were evokedby applying the voltage protocol shown in FIG. 13A.

FIG. 14A-14B: FIG. 14A shows a representative I/V plot of constantcurrent density in a CIC-1 expressing CHO cell before (circles) andafter (squares) application of 100 μM of the CIC-1 inhibitor,9-anthracenecarboxylic acid (9-AC, Sigma A89405). FIG. 14B shows a I/Vplot of instant tail current density from the same CIC-1 expressing CHOcell as illustrated in FIG. 14A, before (circles) and after (squares)application of 100 μM 9-AC.

FIG. 15 : FIG. 15 shows representative plots of normalized instant tailcurrents from a CIC-1 expressing CHO cell patch before (circles) andafter (squares) application of 100 μM 9-AC. The instant tail currents ateach voltage step were normalized to the maximal tail current obtainedfollowing the (+)120 mV voltage step and fitted to a Boltzmann functionto determine the half activation potential, V½.

DETAILED DESCRIPTION Definitions

The term “halogen” means fluoro, chloro, bromo or iodo. “Halo” meanshalogen.

The term “C₁₋₄-alkyl” refers to a branched or unbranched alkyl grouphaving from one to four carbon atoms, including but not limited tomethyl, ethyl, prop-1-yl, prop-2-yl, 2-methyl-prop-1-yl,2-methyl-prop-2-yl, but-1-yl and but-2-yl.

The term “C₂₋₄-alkenyl” refers to a branched or unbranched alkenyl grouphaving from two to four carbon atoms, two of which are connected by adouble bond, including but not limited to ethenyl, propenyl,isopropenyl, butenyl and isobutenyl.

The term “C₂₋₄-alkynyl” refers to a branched or unbranched alkynyl grouphaving from two to four carbon atoms, two of which are connected by atriple bond, including but not limited to ethynyl, propynyl and butynyl.

The term “C₃₋₄-cycloalkyl” refers to a group having three to four carbonatoms, including but not limited to cyclopropyl, cyclobutyl andcyclopropylmethyl.

The term “C₁₋₈-alk(en/yn)yl” means C₁₋₈-alkyl, C₂₋₈-alkenyl orC₂₋₈-alkynyl; wherein:

-   -   The term “C₁₋₈-alkyl” refers to a branched or unbranched alkyl        group having from one to eight carbon atoms, including but not        limited to methyl, ethyl, prop-1-yl, prop-2-yl,        2-methyl-prop-1-yl, 2-methyl-prop-2-yl, 2,2-dimethyl-prop-1-yl,        but-1-yl, but-2-yl, 3-methyl-but-1-yl, 3-methyl-but-2-yl,        pent-1-yl, pent-2-yl, pent-3-yl, hex-1-yl, hex-2-yl, hex-3-yl,        2-methyl-4,4-dimethyl-pent-1-yl and hept-1-yl;    -   The term “C₂₋₈-alkenyl” refers to a branched or unbranched        alkenyl group having from two to eight carbon atoms and one        double bond, including but not limited to ethenyl, propenyl, and        butenyl; and    -   The term “C₂₋₈-alkynyl” refers to a branched or unbranched        alkynyl group having from two to eight carbon atoms and one        triple bond, including but not limited to ethynyl, propynyl and        butynyl.

The term “C₃₋₆-cycloalk(en)yl” means C₃₋₆-cycloalkyl orC₃₋₆-cycloalkenyl, wherein:

-   -   The term “C₃₋₆-cycloalkyl” refers to a group having three to six        carbon atoms including a monocyclic or bicyclic carbocycle,        including but not limited to cyclopropyl, cyclopentyl,        cyclopropylmethyl and cyclohexyl;    -   The term “C₃₋₆-cycloalkenyl” refers to a group having three to        six carbon atoms including a monocyclic or bicyclic carbocycle        having three to six carbon atoms and at least one double bond,        including but not limited to cyclobutenylmethyl, cyclopentenyl,        cyclohexenyl

The term “half-life” as used herein is the time it takes for thecompound to lose one-half of its pharmacologic activity. The term“plasma half-life” is the time that it takes the compound to loseone-half of its pharmacologic activity in the blood plasma.

The term “treatment” refers to the combating of a disease or disorder.“Treatment” or “treating,” as used herein, includes any desirable effecton the symptoms or pathology of a disease or condition as describedherein, and may include even minimal changes or improvements in one ormore measurable markers of the disease or condition being treated.“Treatment” or “treating” does not necessarily indicate completeeradication or cure of the disease or condition, or associated symptomsthereof. In some embodiments, the term “treatment” encompassesamelioration and prevention.

The term “amelioration” refers to moderation in the severity of thesymptoms of a disease or condition. Improvement in a patient'scondition, or the activity of making an effort to correct, or at leastmake more acceptable, conditions that are difficult to endure related topatient's conditions is considered “ameliorative” treatment.

The term “prevent” or “preventing” refers to precluding, averting,obviating, forestalling, stopping, or hindering something fromhappening, especially by advance action.

The term “reversal” or “reversing” refers to the ability of a compoundto restore nerve-stimulated force in skeletal muscle exposed either exvivo or in vivo to a non-depolarizing neuromuscular blocking agent oranother pharmaceutical that is able to depress neuromusculartransmission.

The term “ester hydrolysing reagent” refers to a chemical reagent whichis capable of converting an ester functional group to a carboxylic acidwith elimination of the alcohol moiety of the original ester, includingbut not limited to acid, base, a fluoride source, PBr₃, PCl₃ and lipaseenzymes.

The term “non-depolarizing blockers” refers to pharmaceutical agentsthat antagonize the activation of acetylcholine receptors at thepost-synaptic muscle fibre membrane by blocking the acetylcholinebinding site on the receptor. These agents are used to blockneuromuscular transmission and induce muscle paralysis in connectionwith surgery.

The term “recovery of force in muscle with neuromuscular dysfunction”refers to the ability of a compound to recover contractile force innerve-stimulated healthy rat muscle after exposure to submaximalconcentration of (115 nM) tubocurarine for 90 mins. Recovery of force isquantified as the percentage of the force prior to tubocurarine that isrecovered by the compound.

The term “total membrane conductance (Gm)” is the electrophysiologicalmeasure of the ability of ions to cross the muscle fibre surfacemembrane. It reflects the function of ion channels that are active inresting muscle fibres of which CIC-1 is known to contribute around 80%in most animal species.

Composition

It is within the scope of the present invention to provide a compositionfor use in treating, ameliorating and/or preventing neuromusculardisorders characterized in that the neuromuscular function is reduced.As disclosed herein, inhibition of CIC-1 surprisingly improves orrestores neuromuscular function. The compositions of the presentinvention comprise compounds capable of inhibiting the CIC-1 channelthereby improving or restoring neuromuscular function.

In one aspect, the invention relates to a composition comprising acompound of Formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂; wherein        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, S(O)₂R₁₂,            cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀,            cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀, —S(O)R₁₂, S(O)₂R₁₂, cyano,            O—R₁₁, fluorinated C₁₋₃, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl for use in treating, ameliorating            and/or preventing a neuromuscular disorder.

In one embodiment A is a monocyclic or bicyclic aromatic orheteroaromatic ring. A may for example be a monocyclic ring comprising 5to 6 carbon atoms or a bicyclic ring comprising 8 to 10 C-atoms. In oneembodiment A is five-membered or six-membered aromatic ring. A can alsobe a five-membered or six-membered heteroaromatic ring. In a preferredembodiment A is phenyl or naphthyl.

The heteroaromatic ring may for example comprise S, O or N atoms. In oneembodiment A is a five or six-membered aromatic ring comprising at leastone N. In one embodiment A is a five-membered heteroaromatic ringcomprising an S and four C atoms. In another embodiment A is afive-membered heteroaromatic ring comprising an O and four C atoms.

In one aspect, the invention relates to a composition comprising acompound of Formula (I.2):

-   -   wherein:        -   R¹ is selected from the group consisting of hydrogen, F, Cl,            Br, I, —CN, —CF₃, Cl₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl,            C₄ cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;        -   with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In one aspect, the invention relates to a compound of Formula (Ia):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅            alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl,            each of which may be optionally substituted with one or            more, identical or different, substituents R⁵;        -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl            optionally substituted with one or more, identical or            different, substituents R⁷, C₃₋₆ cycloalkyl optionally            substituted with one or more, identical or different,            substituents R⁷, phenyl optionally substituted with one or            more, identical or different, substituents R⁸ and benzyl            optionally substituted with one or more, identical or            different, substituents R⁸;        -   R⁵ is independently selected from the group consisting of            deuterium, F, OC₁₋₅ alkyl optionally substituted with one or            more, identical or different, substituents R⁷, OC₃₋₅            cycloalkyl optionally substituted with one or more,            identical or different, substituents R⁷, and OH;        -   R⁶ is independently selected from the group consisting of            hydrogen and deuterium;        -   R⁷ is independently selected from the group consisting of            deuterium and F;        -   R⁸ is independently selected from the group consisting of            deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and        -   n is an integer 0, 1, 2, 3 or 4;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;    -   with the proviso that:        -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is            1 or 2, then R³ is not methyl;        -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is            1, then R³ is not ethyl;        -   when R¹ is Cl, R⁴ is H or Me or 4-methoxyphenyl or            4-nitrophenyl, R⁵ is H, R⁶ is H and n is 0, then R³ is not            methyl;        -   when R¹ is Br, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³            is not methyl or isopropyl;        -   when R¹ is Br, R⁴ is Me, R⁵ is H, R⁶ is H and n is 0, then            R³ is not isopropyl; and        -   when R¹ is I, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³            is not methyl.

In an embodiment, when R³ is Me, R⁴ is Et, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, —CN or —CF₃. In an embodiment, when R² is Cl,R³ is Me, R⁴ is Me, Et, cyclohexyl, cyclopentyl or n-Butyl, R⁵ is H, R⁶is H and n is 1, then R¹ is not Cl.

In an embodiment, when R³ is Me, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, I, —CH₃ or —CF₃.

In an embodiment, when R¹ is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R³ is not Et, n-propyl or isopropyl. In an embodiment, when R¹ isBr, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is not cyclopropyl,1,1-difluoroethan-2-yl, 1-methoxypropan-2-yl or 1-ethoxycyclobutan-3-yl.

In one embodiment, the invention relates to a composition comprising acompound of Formula (II):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;

-   -   wherein        -   Y is selected from the group consisting of O, NH, N—CHs,            CH₂, CH₂—O, S and SO₂;        -   X₁, X₂ and X₃ are selected from the group consisting of, CH            and N;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, S(O)₂R₁₂,            cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a C₃₋₆-cycloalk(en)yl or a            halo-C₃₋₆-cycloalk(en)yl;        -   R₄ is as defined in embodiment 1 below;        -   m is as defined in embodiment 1 below;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀, —S(O)R₁₂, S(O)₂R₁₂, cyano,            O—R₁₁, fluorinated C₁₋₃, nitro and halo;

R₉, R₁₀ and R₁₁ are independently selected from H, C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl whereas R₁₂ is selected from C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl for use in treating, ameliorating and/or preventinga neuromuscular disorder.

Y is selected from the group consisting of O, NH, N—CHs, CH₂, CH₂—O, Sand SO₂. Thus Y may be O, NH, N—CHs, CH₂, CH₂—O, S or SO₂. In onepreferred embodiment Y is selected from the group consisting of O, NH,CH₂, S, and SO₂. In a particular embodiment Y is O.

X₁, X₂ and X₃ are selected from the group consisting of, CH and N. Inone embodiment X₁ is N, X₂ is N or X₃ is N. In another preferredembodiment X₁ is N. In particular embodiment X₂ is N.

R₄ is selected from the group consisting of H, C₁₋₆-alk(en/yn)yl,C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀, —NR₁₀—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀, cyano, O—R₁₁, fluorinated C₁₋₃, nitro and halo,wherein R₉, R₁₀ and R₁₁ are independently selected from H,C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl whereas R₁₂ is selected fromC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl

In one embodiment R₄ is selected from the group consisting of H,C₁₋₆-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl. In an embodiment thereof R₄is selected from the group consisting of H, C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl, from the group consisting of H, C₁₋₄-alk(en)yl andC₃₋₆-cycloalk(en)yl or from the group consisting of H, C₁₋₄-alkyl andC₃₋₆-cycloalk(en)yl. In one embodiment R₄ is selected from the groupconsisting of H and C₁₋₄-alkyl.

In another embodiment R₄ is selected from the group consisting ofNR₉—CO—R₁₀, —NR₁₀—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀or O—R₁₁, wherein R₉, R₁₀ and R₁₁ are independently selected from H,C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl whereas R₁₂ is selected fromC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl. R₉, R₁₀ and R₁₁ may forexample be independently selected from H and C₁₋₄-alkyl or from thegroup consisting of H and C₁₋₃-alkyl. In one embodiment R₉, R₁₀ and R₁₁are independently selected from H and —CH₃.

In another embodiment R₄ is selected from the group consisting of cyano,fluorinated C₁₋₃, nitro and halo. In one embodiment R₄ is selected fromthe group consisting of Cl, Br, I or F. In one embodiment R₄ is selectedfrom the group consisting of Cl and Br.

R₄ can be located in either ortho-meta or para-position with respect toY.

m can be 0, 1, 2, 3, 4 or 5. In one embodiment m is 0, 1, 2, 3 or 4,such as 0, 1, 2 or 3 or such as 0, 1 or 2. In another embodiment m is 0or 1.

In one embodiment R₁ and R₂ are independently selected from the groupconsisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉, wherein

-   -   R₃ is selected from the group consisting of H, C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀,        —S(O)R₁₂, S(O)₂R₁₂, cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro        and halo;    -   R₅ is selected from the group consisting of C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀,        —S(O)R₁₂, S(O)₂R₁₂, cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro        and halo; and    -   R₉, R₁₀ and R₁₁ are independently selected from H,        C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl whereas R₁₂ is        selected from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl.

In one embodiment R₃ and/or R₅ is selected from the group consisting ofH, C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl. In another embodiment R₃is selected from the group consisting of H, C₁₋₆-alkyl andC₃₋₇-cycloalkyl. In yet another embodiment R₃ is selected from the groupconsisting of H, C₁₋₆-alkyl, such as from the group consisting of H andC₁₋₄-alkyl. In another embodiment R₃ is selected from the groupconsisting of H and CH₃.

In another embodiment R₁ and R₂ are independently selected from thegroup consisting of H, C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl.C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted with up tothree substituents selected from the group consisting of —NR₉—CO—R₁₀,—N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀,—S(O)R₁₂, S(O)₂R₁₂, cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro andhalo.

R₉, R₁₀ and R₁₁ are independently selected from H, C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl whereas R₁₂ is selected from C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl It is appreciated that R₁ is different from R₂.

In a preferred embodiment R₁ is selected from the group consisting of Hand —CH₃. In a more preferred embodiment R₁ is H.

In one embodiment R₁ is H and R₂ is selected from the group consistingof H, C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl. C₁₋₈-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl may be substituted with up to three substituentsselected from the group consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂,—CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, S(O)₂R₁₂,cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo, wherein R₉, R₁₀and R₁₁ are independently selected from H, C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl whereas R₁₂ is selected from C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl.

In another embodiment R₁ is H and R₂ is selected from the groupconsisting of H, C₁₋₄-alk(en)yl, C₃₋₆-cycloalk(en)yl, wherein saidC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted with up totwo substituents selected from the group consisting of —NR₉—CO—R₁₀,—N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀,—S(O)R₁₂, S(O)₂R₁₂, cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro andhalo, wherein R₉, R₁₀ and R₁₁ are independently selected from H,C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl whereas R₁₂ is selected fromC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl.

In yet another embodiment R₁ is H and R₂ is selected from the groupconsisting of H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl and amino-C₁₋₄-alkyl,wherein said C₁₋₄-alkyl and C₃₋₆-cycloalkyl may be substituted withO—R₁₁, wherein R₁₁ is as defined above. In a specific embodiment R₁₁ is—CH₃.

In one embodiment R₁ and R₂ are independently selected from the groupconsisting of H and CH₃. In a preferred embodiment R₁ is H and R₂ isselected from the group consisting of H, C₁₋₆-alkyl and C₃₋₇-cycloalkyl.For example, R₁ is H and R₂ is selected from the group consisting of H,C₁₋₄-alkyl and C₃₋₅-cycloalkyl. In a further preferred embodiment R₁ isH and R₂ is selected from the group consisting of H, C₁₋₄-alkyl. In aparticular embodiment, R₁ is H and R₂ is selected from the groupconsisting of H, —CH₃, —CH(CH₃)₂ and cyclopropyl. In an embodimentthereof R₁ is H and R₂ is —CH(CH₃)₂.

In a specific embodiment R₂ is —CH(CH₃)CH₂—O—CH₃. In particular, R₁ is Hand R₂ is —CH(CH₃)CH₂—O—CH₃.

In a preferred embodiment the compound is the S-enantiomer with respectto the C-atom to which R₂ is bound.

R₁ and R₂ are in one embodiment linked to form a C₃₋₆-cycloalk(en)yl ora halo-C₃₋₆-cycloalk(en)yl. In one particular embodiment R₁ and R₂ arelinked to form a 035-cycloalk(en)yl or a halo-C₃₋₅-cycloalk(en)yl. Inanother embodiment R₁ and R₂ are linked to form a C₃₋₄-cycloalk(en)yl ora halo-C₃₋₄-cycloalk(en)yl. In a preferred embodiment R₁ and R₂ arelinked to form a cyclopropyl or a halo-cyclopropyl. In a more preferredembodiment R₁ and R₂ are linked to form a cyclopropyl.

In one aspect, the invention relates to a composition comprising acompound of Formula (II.2):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H and C₁₋₅            alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;        -   with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In one aspect, the invention relates to a compound of Formula (IIa):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅            alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl,            each of which may be optionally substituted with one or            more, identical or different, substituents R⁵;        -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl            optionally substituted with one or more, identical or            different, substituents R⁷, C₃₋₆ cycloalkyl optionally            substituted with one or more, identical or different,            substituents R⁷, phenyl optionally substituted with one or            more, identical or different, substituents R⁸ and benzyl            optionally substituted with one or more, identical or            different, substituents R⁸;        -   R⁵ is independently selected from the group consisting of            deuterium, F, OC₁₋₅ alkyl optionally substituted with one or            more, identical or different, substituents R⁷, OC₃₋₅            cycloalkyl optionally substituted with one or more,            identical or different, substituents R⁷, and OH;        -   R⁶ is independently selected from the group consisting of            hydrogen and deuterium;        -   R⁷ is independently selected from the group consisting of            deuterium and F;        -   R⁸ is independently selected from the group consisting of            deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and        -   n is an integer 0, 1, 2, 3 or 4;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;    -   with the proviso that:        -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is            1 or 2, then R³ is not methyl;        -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is            1, then R³ is not ethyl;        -   when R¹ is Cl, R⁴ is H or Me or 4-methoxyphenyl or            4-nitrophenyl, R⁵ is H, R⁶ is H and n is 0, then R³ is not            methyl;        -   when R¹ is Br, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³            is not methyl or isopropyl;        -   when R¹ is Br, R⁴ is Me, R⁵ is H, R⁶ is H and n is 0, then            R³ is not isopropyl; and        -   when R¹ is I, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³            is not methyl.

In an embodiment, when R³ is Me, R⁴ is Et, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, —CN or —CF₃. In an embodiment, when R² is Cl,R³ is Me, R⁴ is Me, Et, cyclohexyl, cyclopentyl or n-Butyl, R⁵ is H, R⁶is H and n is 1, then R¹ is not Cl.

In an embodiment, when R³ is Me, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, I, —CH₃ or —CF₃.

In an embodiment, when R¹ is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R³ is not Et, n-propyl or isopropyl. In an embodiment, when R¹ isBr, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is not cyclopropyl,1,1-difluoroethan-2-yl, 1-methoxypropan-2-yl or 1-ethoxycyclobutan-3-yl.

In a particular embodiment R₁ is H and R₂ is —CH(CH₃)₂ and wherein saidcompound is the S-enantiomer with respect to the C-atom to which R₂ isbound as shown in formula (III):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein, m, Y, X₁, X₂ and X₃ and R₄ are as defined above. For example X₁is N, X₂ is N or X₃ is N. In another embodiment X₁, X₂ and X₃ is C. R₄may for example be selected from the group consisting of H, halo, cyano,—CHO, C₁₋₄-alk(en)yl, halo-C₁₋₄-alk(en)yl, —O—C₁₋₄-alk(en)yl

In a preferred embodiment m is 0, 1 or 2. In one embodiment m is 0 or 1.For example m is 1.

In one aspect, the invention relates to a compound of Formula (III.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, I, and -oxime optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In an embodiment of the present invention the compound of Formula (I) isfurther defined by Formula (IV):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein A, R₂ and R₄ are as defined above. In one embodiment R₂ isC₁₋₆-alkyl or C₃₋₇-cycloalkyl. For example A is a monocyclic ring suchas a phenyl. It is preferred that R₄ is in ortho- or meta position.

In one aspect, the invention relates to a compound of Formula (IV.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, and I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Thus, in an embodiment thereof, the compound of Formula (IV) is furtherdefined by Formula (V):

wherein R₂ and R₄ are as defined above.

In one aspect, the invention relates to a compound of Formula (V.2):

-   -   wherein:        -   R¹ is Br, Cl or I;        -   R² is independently deuterium, F, Cl, Br, or I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one embodiment thereof, the compound of Formula (V) is furtherdefined by Formula (VI):

wherein R₄ is as defined above. It is preferred the R₄ is in ortho- ormeta position.

In one aspect, the invention relates to a compound of Formula (VI.2):

-   -   wherein:        -   R¹ is Br, Cl or I;        -   R² is independently deuterium, F, Cl, Br, or I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In another embodiment of the present invention the compound of Formula(I) is further defined by Formula (VII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein m is 2 and X₁, X₂, Y, R₂ and R₄ are as defined above.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅            alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl            each of which may be optionally substituted with one or            more, identical or different, substituents R⁵;        -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl            optionally substituted with one or more, identical or            different, substituents R⁷, C₃₋₆ cycloalkyl optionally            substituted with one or more, identical or different,            substituents R⁷, phenyl optionally substituted with one or            more, identical or different, substituents R⁸ and benzyl            optionally substituted with one or more, identical or            different, substituents R⁸;        -   R⁵ is independently selected from the group consisting of            deuterium, F, —OC₁₋₅ alkyl optionally substituted with one            or more, identical or different, substituents R⁷ and —OC₃₋₅            cycloalkyl optionally substituted with one or more,            identical or different, substituents R⁷;        -   R⁶ is selected from the group consisting of hydrogen and            deuterium;        -   R⁷ is independently selected from the group consisting of            deuterium and F;        -   R⁸ is independently selected from the group consisting of            deuterium, methoxy, nitro, cyano, Cl, Br, I and F;        -   R⁹ is deuterium; and        -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of Cl and Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl        optionally substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, C₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which is substituted with one or more, identical or        different, substituents R⁵; and    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R₇;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₃₋₅ cycloalkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl and C₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I, —CN, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        C₃₋₄ cycloalkyl and —S—CH₃;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br and I;    -   R³ is selected from the group consisting of fluoromethyl,        fluoroethyl and fluoropropyl, each of which may be optionally        substituted with one or more deuterium;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one embodiment, R¹ is selected from the group consisting of F, Cl,Br, and I, such as R¹ is selected from the group consisting of Cl andBr. In one embodiment, R¹ is Br.

In one embodiment, R² is selected from the group consisting ofdeuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime optionally substitutedwith C₁ alkyl. In one embodiment, R² is selected from the groupconsisting of F, Cl and Br. In one embodiment, R² is deuterium or F,such as deuterium. In one embodiment, R² is hydrogen or deuterium. Inanother embodiment, R² is an oxime, such as an aldoxime. Said oxime maybe substituted with C₁ alkyl.

In some embodiments, R¹ is different from R², such as R¹ is Cl and R² isF; R¹ is Cl and R² is Br; such as R¹ is Cl and R² is H; such as R¹ is Cland R² is D; such as R¹ is Br and R² is F; such as R¹ is Br and R² isCl; such as R¹ is Br and R² is H; such as R¹ is Br and R² is D.

In some embodiments, R¹ and R² are the same, such as R¹ is Cl and R² isCl or such as R¹ is Br and R² is Br.

In one embodiment, R³ is selected from the group consisting of C₁₋₃alkyl and C₃₋₄ cycloalkyl optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R³ isselected from the group consisting of C₁₋₃ alkyl and C₃₋₄ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁵, with the proviso that when R¹ is Cl, R² is Cl, R⁴ is H,R⁶ is H, n is 0 and R³ is ethyl, then said ethyl is substituted with oneor more, identical or different, substituents R⁵. In one embodiment,said C₁₋₃ alkyl is methyl.

In one embodiment, R³ is selected from the group consisting of 02-3alkyl and C₃₋₄ cycloalkyl optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R³ isselected from the group consisting of 02-3 alkyl and C₃₋₄ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁵, with the proviso that when R¹ is Cl, R² is Cl, R⁴ is H,R⁶ is H, n is 0 and R³ is ethyl, then said ethyl is substituted with oneor more, identical or different, substituents R⁵.

In one embodiment, R³ is selected from the group consisting of methyl,ethyl, n-propyl or isopropyl optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R³ is methylsubstituted with one or more, identical or different, substituents R⁵;such as R³ is methyl. In one embodiment, R³ is ethyl optionallysubstituted with one or more, identical or different, substituents R⁵with the proviso that when R¹ is Cl, R² is Cl, R⁴ is H, R⁶ is H, n is 0,and R³ is ethyl, then said ethyl is substituted with one or more,identical or different, substituents R⁵; such as R³ is ethyl. In oneembodiment, R³ is n-propyl optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R³ isisopropyl optionally substituted with one or more, identical ordifferent, substituents R⁵. In one embodiment, R³ is n-propyl orisopropyl.

In one embodiment, R³ is C₁₋₅ alkyl substituted with one or more F.Thus, in one embodiment, R³ is selected from the group consisting offluoromethyl, fluoroethyl and fluoropropyl. In one embodiment, R³ isselected from the group consisting of —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F,—CH₂CHF₂ and —CH₂CF₃, preferably —CH₂F. In one embodiment, R³ isselected from the group consisting of fluoromethyl, difluoromethyl,2-fluoroeth-1-yl, (1S)-1-fluoroeth-1-yl, (1R)-1-fluoroeth-1-yl,(1S)-1,2-difluoroeth-1-yl, (1R)-1,2-difluoroeth-1-yl, 3-fluoroprop-1-yl,(1S)-1-fluoroprop-1-yl, (1R)-1-fluoroprop-1-yl, (2S)-2-fluoroprop-1-yl,(2R)-2-fluoroprop-1-yl, (1S)-2-fluoro-1-methyl-eth-1-yl,(1S)-2-fluoro-1-methyl-eth-1-yl and 2-fluoro-1-(fluoromethyl)eth-1-yl.In one embodiment, R³ is selected from the group consisting offluoromethyl, 2-fluoroeth-1-yl, (1S)-1-fluoroeth-1-yl and(1R)-1-fluoroeth-1-yl.

In one embodiment, R³ is cyclopropyl optionally substituted with one ormore, identical or different, substituents R⁵. In one embodiment, R³ iscyclopropylmethyl optionally substituted with one or more, identical ordifferent, substituents R⁵. In one embodiment, R³ is cyclobutyloptionally substituted with one or more, identical or different,substituents R⁵.

In one embodiment, R³ is C₃₋₅ cycloalkyl, optionally substituted withone or more F. Thus, in one embodiment, R³ is selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl and cyclobutylmethyl, optionally substituted with oneor more F.

In one embodiment, R³ is C₂₋₅ alkenyl, optionally substituted with oneor more, identical or different, substituents R⁵. In one embodiment,said C₂₋₅ alkenyl is a cycloalkenyl. In one embodiment, R³ is selectedfrom the group consisting of ethenyl, propenyl, isopropenyl, butenyl,isobutenyl and pentenyl, optionally substituted with one or more F.

In one embodiment, R³ is optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R⁵ isindependently selected from the group consisting of deuterium, F, —OC₁₋₅alkyl optionally substituted with one or more, identical or different,substituents R⁷ and —OC₃₋₅ cycloalkyl optionally substituted with one ormore, identical or different, substituents R⁷.

In one embodiment, R⁵ is independently deuterium or F. In oneembodiment, R³ is substituted with one or more deuterium, such as R³ isselected from the group consisting of trideuteriomethyl,1,2-dideuterioethyl and 1,1,2,2-tetradeuterioethyl.

In one embodiment, R³ is substituted with one fluorine.

In one embodiment, R³ is substituted with one or more —OC₁₋₅ alkylgroups optionally substituted with one or more, identical or different,substituents R⁷; such as R³ is substituted with one or more —OMe groupsoptionally substituted with one or more, identical or different,substituents R⁷; such as R³ is substituted with one or more —OEt groupsoptionally substituted with one or more, identical or different,substituents R⁷; or such as R³ is substituted with one or more —OC₃₋₅cycloalkyl groups optionally substituted with one or more, identical ordifferent, substituents R⁷.

In one embodiment, R⁴ is H forming an acid. In one embodiment, said acidis deprotonated. Said deprotonated acid may interact with a cation, suchas an alkali metal cation. In one embodiment, R⁴ is the sodiumcounterion.

In one embodiment, R⁶ is H. In another embodiment, R⁶ is D.

In one embodiment, n is an integer 0, 1, 2, 3, or 4, such as n is 0;such as n is 1; such as n is 2.

In one embodiment,

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which may        be optionally substituted with one or more F; and    -   R⁴ is selected from the group consisting of H and C₁₋₅ alkyl,        preferably H;    -   n is 0;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

In one embodiment,

-   -   R¹ is Cl;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, C₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

In one embodiment,

-   -   R¹ is Cl;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R₅;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0.

In one embodiment,

-   -   R¹ is Cl;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

In one embodiment,

-   -   R¹ is Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, C₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

In one embodiment,

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0.

In one embodiment,

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

In one embodiment thereof Formula (VII) is further defined by Formula(VIII)

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein m, X₂, Y, R₂ and R₄ are as defined above. For example, in apreferred embodiment Y is O. Further, it is preferred that R₂ isselected from the group consisting of H and C₁₋₄-alkyl. R₄ is in oneembodiment selected from the group consisting of H, —CH₃ and halogen.

In a specific embodiment the compound of Formula (VIII) is furtherdefined by Formula (IX):

In one embodiment of the present invention the compound of Formula (VII)is further defined by Formula (X):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)CH₂—O—CH₃, —CH₂—CH₂—CH₃, —CH₂—NH₂,—CH₂—CHF₂, —CH₂—CF₃, —CH₂—NH—CO—CH₃ and —CH₂—NH—SO₂—CH₃ and cyclopropyl,and R₄ is selected from the group consisting of H, Br, Cl, F and I. In apreferred embodiment R₂ is —CH₃ or —CH(CH₃)₂; and R₄ is selected fromthe group consisting of H, Br, Cl, F and I. In particular, R₂ is—CH(CH₃)₂ and R₄ is selected from the group consisting of H, Br, Cl, Fand I.

In specific embodiments Formula (VII) is further defined by any one ofFormulas (XI) to (XXVIII):

In another embodiment of the present invention the compound of Formula(VII) is further defined by Formula (XXIX):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I. In a preferred embodiment R₂is —CH₃ or —CH(CH₃)₂; and R₄ is selected from the group consisting of H,Br, Cl, F and I. In another preferred embodiment R₂ is —CH₃ or —CH(CH₃)₂and R₄ is selected from the group consisting of H, Br, Cl and F. It isfurther preferred that the compound of Formula (X) is the S-enantiomerwith respect to the C-atom to which R₂ is bound. This embodiment isexemplified by Formulas (XXIII) and (XXIV), where R₂ is —CH₃ and R₄ isCl or Br.

Thus, in one embodiment the compound of Formula (XXIX) is furtherdefined by Formula (XXX):

In another specific embodiment the compound of Formula (VII) is furtherdefined by Formula (XXXI):

In one embodiment of the present invention Y is SO₂. In particular, thecompound of Formula (VII) can be further defined by Formula (XXXII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I. In a preferred embodiment R₂is —CH₃ or —CH(CH₃)₂; and R₄ is selected from the group consisting of H,Br, Cl, F and I. In another preferred embodiment R₂ is —CH₃ or —CH(CH₃)₂and R₄ is selected from the group consisting of H, Br, Cl and F.

In a specific embodiment the compound of Formula (XXXII) is defined byFormula (XXXIII):

As mentioned above, in one embodiment of the present A can be anaphthyl. In one embodiment Y is O. Thus, in a preferred embodiment ofthe present invention the compound of Formula (I) is further defined byFormula (XXXIV):

or a salt or tautomer thereof;wherein R₂ and X₁ are as defined above; and R₄ and R′₄ are independentlyselected from the group consisting of H, halo, cyano, hydroxy, —CHO,C₁₋₆-alk(en/yn)yl, halo-C₁₋₆-alk(en/yn)yl, O—C₁₋₆-alk(en/yn)yl. In apreferred embodiment R₂ is selected from the group consisting of —CH₃,—CH₂—CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂. Preferably R₂is CHs or —CH(CH₃)₂. It is preferred that R₄ and R′₄ are individuallyselected from the group consisting of H, Br, Cl, F and I. In anotherpreferred embodiment R₄ and/or R′₄ are H. It is further preferred thatX₁ is N or C.

In a particular embodiment R₂ is selected from the group consisting of—CH₃, —CH₂—CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂; X₁ is Nor C; and R₄ and R′₄ are individually selected from the group consistingof H, Br, Cl, F and I. In a particular embodiment Formula (XXXIV) isfurther defined by Formula (XXXV):

In specific embodiments of the present invention the compound of Formula(I) is further defined by any one of Formulas (XXXVI) to (LIX):

In a specific embodiment, the compound is selected from the groupconsisting of:

Compounds

In one aspect, the invention relates to the use of the followingcompounds in treating, ameliorating and/or preventing a neuromusculardisorder. In one aspect, the invention relates to the use of thefollowing compounds in reversing and/or ameliorating a neuromuscularblockade.

Another aspect of the present invention relates to a compound of Formula(I):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂; wherein        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, S(O)₂R₁₂,            cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀,            cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀, —S(O)R₁₂, S(O)₂R₁₂, cyano,            O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl

In one embodiment thereof, A is a monocyclic or bicyclic aromatic orheteroaromatic ring. For example, A can be a five-membered orsix-membered aromatic ring. In one embodiment A is phenyl, or naphthyl.

in one aspect, the invention relates to a compound of Formula (I.2):

-   -   wherein:        -   R¹ is selected from the group consisting of hydrogen, F, Cl,            Br, I, —CN, —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;            with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In another embodiment of the present invention, the compound of Formula(I) is further defined by Formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   Y is selected from the group consisting of O, NH, N—CH₃,            CH₂, CH₂—O, S and SO₂;        -   X₁, X₂ and X₃ are selected from the group consisting of, CH            and N;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, S(O)₂R₁₂,            cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a C₃₋₆-cycloalk(en)yl or a            halo-C₃₋₆-cycloalk(en)yl;        -   R₄ is as defined in embodiment 1 below;        -   m is as defined in embodiment 1 below;        -   R⁵ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀, —S(O)R₁₂, S(O)₂R₁₂, cyano,            O—R₁₁, fluorinated C₁₋₃, nitro and halo; or R₁ and R₂ are            linked to form a ring;    -   R₉, R₁₀ and R₁₁ are independently selected from H,        C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl whereas R₁₂ is        selected from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl; for use        in treating, ameliorating and/or preventing a neuromuscular        disorder.

In a preferred embodiment R₁ is selected from the group consisting of Hand —CH₃. In a particular embodiment R₁ is H.

Thus, in one embodiment R₁ is H and R₂ is selected from the groupconsisting of H, C₁₋₄-alk(en)yl, C₃₋₆-cycloalk(en)yl, wherein saidC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted with up totwo substituents selected from the group consisting of —NR₉—CO—R₁₀,—N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀,—S(O)R₁₂, S(O)₂R₁₂, cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro andhalo, wherein R₉, R₁₀ and R₁₁ are independently selected from H,C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl whereas R₁₂ is selected fromC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl

Thus, in another embodiment R₁ is H and R₂ is selected from the groupconsisting of H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl and amino-C₁₋₄-alkyl,wherein said C₁₋₄-alkyl and C₃₋₆-cycloalkyl may be substituted withO—R₁₁, wherein R₁₁ is as defined above. In one embodiment R₁₁ is —CH₃.In another embodiment R₂ is —CH(CH₃)CH₂—O—CH₃.

In a preferred embodiment of the present invention R₁ is H and R₂ isselected from the group consisting of H, C₁₋₆-alkyl and C₃₋₇-cycloalkyl.For example, R₁ is H and R₂ is selected from the group consisting of H,—CH₃, —CH(CH₃)₂ and cyclopropyl. In a particular embodiment, R₁ is H andR₂ is —CH(CH₃)₂.

It is preferred that R₁ is different from R₂.

It is appreciated that the compound as defined herein is theS-enantiomer with respect to the C-atom to which R₂ is bound.

In one aspect, the invention relates to a compound of Formula (II.2):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H and C₁₋₅            alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;            with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In one embodiment thereof, R₁ is H and R₂ is C₁₋₆-alkyl orC₃₋₇-cycloalkyl and wherein said compound is the S-enantiomer withrespect to the C-atom to which R₂ is bound as shown in Formula (III):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein, Y, X₁, X₂ and X₃ and R₄ are as defined above.

In one preferred embodiment of the invention, R₄ is selected from thegroup consisting of H, halo, cyano, —CHO, C₁₋₄-alk(en)yl,halo-C₁₋₄-alk(en)yl, —O—C₁₋₄-alk(en)yl.

In one embodiment m is 0, 1 or 2. For example m is 1.

In one embodiment of the invention X₁ is N, X₂ is N or X₃ is N. Inanother embodiment X₁, X₂ and X₃ is C.

In one aspect, the invention relates to a compound of Formula (III.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, I, and -oxime optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H.

The compound may in one embodiment be defined by Formula (I), which isfurther defined by Formula (IV):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein A, R₂ and R₄ are as defined above.

In one aspect, the invention relates to a compound of Formula (IV.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, and I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₆            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₆ alkyl;            preferably H.

Also, the compound of Formula (IV) can be further defined by Formula(V):

wherein R₂ and R₄ are as defined above. It is preferred that R₂ isC₁₋₆-alkyl or C₃₋₇-cycloalkyl.

In one aspect, the invention relates to a compound of Formula (V.2):

-   -   wherein:        -   R¹ is Br, Cl or I;        -   R² is independently deuterium, F, Cl, Br, or I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H.

In one embodiment thereof, the compound of Formula (V) is furtherdefined by Formula (VI):

wherein R₄ is as defined above. Preferably, R₄ is in ortho- or metaposition.

In one aspect, the invention relates to a compound of Formula (VI.2):

-   -   wherein:        -   R¹ is Br, Cl or I;        -   R² is independently deuterium, F, Cl, Br, or I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H.

In one embodiment of the present invention the compound of Formula (I)is further defined by Formula (VII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein m is 2 and X₁, X₂, Y, R₂ and R₄ are as defined above.

In an embodiment thereof, the compound of Formula (VII) is furtherdefined by Formula (VIII)

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof; wherein m, X₂, Y, R₂ and R₄ are as defined above.

In one preferred embodiment Y is O. It is further preferred that R₂ isselected from the group consisting of H and C₁₋₄-alkyl. Preferably, R₄is selected from the group consisting of H, —CH₃ and halogen. Thus, inone embodiment the compound is further defined by Formula (IX):

In one embodiment the compound of Formula (VII) is further defined byFormula (X):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof; wherein R₂ is selected from the group consisting of —CH₃,—CH₂—CH₃, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)CH₂—O—CHs, —CH₂—CH₂—CH₃,—CH₂—NH₂, —CH₂—CHF₂, —CH₂—CF₃, —CH₂—NH—CO—CH₃ and —CH₂—NH—SO₂—CH₃ andcyclopropyl, and R₄ is selected from the group consisting of H, Br, Cl,F and I.

In specific embodiments, the compound of Formula (VII) is furtherdefined by any one of Formulas (XI) to (XXVIII) as defined herein.

Another embodiment of the present invention relates to a compound ofFormula (VII) that is further defined by Formula (XXIX):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I.

In particular, the compound of Formula (XXIX) is further defined byFormula (XXX):

In one embodiment, the compound of Formula (VII) is further defined byFormula (XXXI):

Also, the compound of Formula (VII) can be further defined by Formula(XXXII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I.

Preferably, the compound of Formula (XXXII) is further defined byFormula (XXXIII):

In another embodiment of the present invention the compound of Formula(I) is further defined by Formula (XXXIV):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂; X₁ is N or C; and R₄ andR′₄ are individually selected from the group consisting of H, Br, Cl, Fand I.

In particular, Formula (XXXIV) can be further defined by Formula (XXXV):

In specific embodiments of the present invention, the compound ofFormula (I) is further defined by any one of Formulas (XXXVI) to (LIX)and compounds A-1 to A-58 and for use in treating, ameliorating and/orpreventing a neuromuscular disorder, and/or for use in reversing and/orameliorating a neuromuscular blockade.

In one embodiment, the compound or the compound for use according to thepresent invention has been modified in order to increase its half-lifewhen administered to a patient, in particular its plasma half-life.

In one embodiment, the compound or the compound for use according to thepresent invention further comprises a moiety conjugated to saidcompound, thus generating a moiety-conjugated compound. In oneembodiment, said moiety-conjugated compound has a plasma and/or serumhalf-life being longer than the plasma and/or serum half-life of thenon-moiety conjugated compound.

In one embodiment, the moiety conjugated to the compound or compound foruse according to the present invention, is one or more type(s) ofmoieties selected from the group consisting of albumin, fatty acids,polyethylene glycol (PEG), acylation groups, antibodies and antibodyfragments

Neuromuscular Disorders

The compositions and compounds of the present invention are used fortreating, ameliorating and/or preventing a neuromuscular disorder, orreversing neuromuscular blockade caused by non-depolarizingneuromuscular blocker or antibiotic agent.

The inventors of the present invention have shown that inhibition ofCIC-1 channels recovers neuromuscular transmission. CIC-1 function maytherefore contribute to muscle weakness in conditions of compromisedneuromuscular transmission.

Thus, in one embodiment of the present invention, the composition foruse as described herein inhibits CIC-1 channels. Thus, it is appreciatedthat compounds of Formula (I) inhibit CIC-1 channels.

The neuromuscular disorder may also include neuromuscular dysfunctions.

Neuromuscular disorders include for example disorders with symptoms ofmuscle weakness and fatigue. Such disorders may include conditions withreduced neuromuscular transmission safety factor. In one embodiment theneuromuscular disorders are motor neuron disorders. Motor neurondisorders are disorders with reduced safety in the neuromusculartransmission. In one embodiment motor neuron disorders are selected fromthe group consisting of amyotrophic lateral sclerosis (ALS), spinalmuscular atrophy (SMA), X-linked spinal and bulbar muscular atrophy,Kennedy's disorder, multifocal motor neuropathy, Guillain-Barrésyndrome, poliomyelitis and post-polio syndrome.

Thus, in one preferred embodiment of the present invention theneuromuscular disorder is ALS. In another preferred embodiment theneuromuscular disorder is SMA. In another preferred embodiment theneuromuscular disorder is Charcot-Marie tooth disease (CMT). In anotherpreferred embodiment the neuromuscular disorder is sarcopenia. In yetanother preferred embodiment, the neuromuscular disorder is criticalillness myopathy (CIM).

As stated above the neuromuscular disorders include for exampledisorders with symptoms of muscle weakness and fatigue. Such disordermay for example include diabetes.

In one embodiment the composition of the present invention is used toprevent neuromuscular disorder. The composition may for example be usedprophylactically against nerve gas that is known to cause symptoms ofmuscle weakness and fatigue.

In another embodiment the neuromuscular disorders is chronic fatiguesyndrome. Chronic fatigue syndrome (CFS) is the common name for amedical condition characterized by debilitating symptoms, includingfatigue that lasts for a minimum of six months in adults. CFS may alsobe referred to as systemic exertion intolerance disorder (SEID), myalgicencephalomyelitis (ME), post-viral fatigue syndrome (PVFS), chronicfatigue immune dysfunction syndrome (CFIDS), or by several other terms.Symptoms of CFS include malaise after exertion; unrefreshing sleep,widespread muscle and joint pain, physical exhaustion, and muscleweakness.

In a further embodiment the neuromuscular disorder is a critical illnesspolyneuropathy or CIM. Critical illness polyneuropathy and CIM areoverlapping syndromes of widespread muscle weakness and neurologicaldysfunction developing in critically ill patients.

The neuromuscular disorder may also include metabolic myopathy andmitochondrial myopathy. Metabolic myopathies result from defects inbiochemical metabolism that primarily affects muscle. These may includeglycogen storage disorders, lipid storage disorder and 3-phosphocreatinestores disorder. Mitochondrial myopathy is a type of myopathy associatedwith mitochondrial disorder. Symptoms of mitochondrial myopathiesinclude muscular and neurological problems such as muscle weakness,exercise intolerance, hearing loss and trouble with balance andcoordination.

In another embodiment the neuromuscular disorder is periodic paralysis,in particular hypokalemic periodic paralysis which is a disorder ofskeletal muscle excitability that presents with recurrent episodes ofweakness, often triggered by exercise, stress, or carbohydrate-richmeals or hyperkalemic periodic paralysis which is an inherited autosomaldominant disorder that affects sodium channels in muscle cells and theability to regulate potassium levels in the blood.

In a preferred embodiment the neuromuscular disorder is a myastheniccondition. Myasthenic conditions are characterized by muscle weaknessand neuromuscular transmission failure. Congenital myasthenia gravis isan inherited neuromuscular disorder caused by defects of several typesat the neuromuscular junction. Myasthenia gravis and Lambert-Eatonsyndrome are also examples of myasthenic condition. Myasthenia gravis iseither an autoimmune or congenital neuromuscular disorder that leads tofluctuating muscle weakness and fatigue. In the most common cases,muscle weakness is caused by circulating antibodies that block AChreceptors at the postsynaptic neuromuscular junction, inhibiting theexcitatory effects of the neurotransmitter ACh on nicotinicAch-receptors at neuromuscular junctions. Lambert-Eaton myasthenicsyndrome (also known as LEMS, Lambert-Eaton syndrome, or Eaton-Lambertsyndrome) is a rare autoimmune disorder that is characterized by muscleweakness of the limbs. It is the result of an autoimmune reaction inwhich antibodies are formed against presynaptic voltage-gated calciumchannels, and likely other nerve terminal proteins, in the neuromuscularjunction.

Thus, in one preferred embodiment of the present invention theneuromuscular disorder is myasthenia gravis. In another preferredembodiment the neuromuscular disorder is Lambert-Eaton syndrome.

Neuromuscular blockade is used in connection with surgery under generalanaesthesia. Reversing agents are used for more rapid and safer recoveryof muscle function after such blockade. Complications with excessivemuscle weakness after blockade during surgery can result in delayedweaning from mechanical ventilation and respiratory complications afterthe surgery. Since such complications have pronounced effects on outcomeof the surgery and future quality of life of patients, there is a needfor improved reversing agents. Thus, in a preferred embodiment theneuromuscular disorder is muscle weakness caused by neuromuscularblockade after surgery. In another preferred embodiment of the presentinvention the composition is used for reversing and/or amelioratingneuromuscular blockade after surgery. Thus, one aspect of the presentinvention relates to a composition comprising a compound of Formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂; wherein        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, S(O)₂R₁₂,            cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀,            cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉R₁₀, —S(O)R₁₂, S(O)₂R₁₂, cyano,            O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl    -   for use in reversing and/or ameliorating a neuromuscular        blockade after surgery.

In one aspect, the invention relates to a compound of Formula (I.2):

-   -   wherein:        -   R¹ is selected from the group consisting of hydrogen, F, Cl,            Br, I, —CN, —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;            or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof, for use in treating,            ameliorating and/or preventing a neuromuscular disorder,            and/or for use in reversing and/or ameliorating a            neuromuscular blockade;            with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In one aspect, the invention relates to the use of compounds of Formula(Ia) in treating, ameliorating and/or preventing a neuromusculardisorder. In one aspect, the invention relates to the use of compoundsof Formula (Ia) in reversing and/or ameliorating a neuromuscularblockade.

In one aspect, the invention relates to a compound of Formula (Ia):

wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R² is independently selected from the group consisting of        hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime        optionally substituted with C₁ alkyl;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷, OC₃₋₅ cycloalkyl        optionally substituted with one or more, identical or different,        substituents R⁷, and OH;    -   R⁶ is independently selected from the group consisting of        hydrogen and deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and    -   n is an integer 0, 1, 2, 3 or 4;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade;        with the proviso that:    -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1 or        2, then R³ is not methyl;    -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1,        then R³ is not ethyl;    -   when R¹ is Cl, R⁴ is H or Me or 4-methoxyphenyl or        4-nitrophenyl, R⁵ is H, R⁶ is H and n is 0, then R³ is not        methyl;    -   when R¹ is Br, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is        not methyl or isopropyl;    -   when R¹ is Br, R⁴ is Me, R⁵ is H, R⁶ is H and n is 0, then R³ is        not isopropyl; and    -   when R¹ is I, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is        not methyl.

In an embodiment, when R³ is Me, R⁴ is Et, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, —CN or —CF₃. In an embodiment, when R² is Cl,R³ is Me, R⁴ is Me, Et, cyclohexyl, cyclopentyl or n-Butyl, R⁵ is H, R⁶is H and n is 1, then R¹ is not C₁.

In an embodiment, when R³ is Me, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, I, —CH₃ or —CF₃.

In an embodiment, when R¹ is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R³ is not Et, n-propyl or isopropyl. In an embodiment, when R¹ isBr, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is not cyclopropyl,1,1-difluoroethan-2-yl, 1-methoxypropan-2-yl or 1-ethoxycyclobutan-3-yl.

In one aspect, the invention relates to a compound of Formula (II.2):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H and C₁₋₅            alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;            or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof, for use in treating,            ameliorating and/or preventing a neuromuscular disorder,            and/or for use in reversing and/or ameliorating a            neuromuscular blockade;            with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

In one aspect, the invention relates to a compound of Formula (IIa):

wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R² is independently selected from the group consisting of        hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime        optionally substituted with C₁ alkyl;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷, OC₃₋₅ cycloalkyl        optionally substituted with one or more, identical or different,        substituents R⁷, and OH;    -   R⁶ is independently selected from the group consisting of        hydrogen and deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and    -   n is an integer 0, 1, 2, 3 or 4;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade;        with the proviso that:    -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1 or        2, then R³ is not methyl;    -   when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1,        then R³ is not ethyl;    -   when R¹ is Cl, R⁴ is H or Me or 4-methoxyphenyl or        4-nitrophenyl, R⁵ is H, R⁶ is H and n is 0, then R³ is not        methyl;    -   when R¹ is Br, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is        not methyl or isopropyl;    -   when R¹ is Br, R⁴ is Me, R⁵ is H, R⁶ is H and n is 0, then R³ is        not isopropyl; and    -   when R¹ is I, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is        not methyl.

In an embodiment, when R³ is Me, R⁴ is Et, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, —CN or —CF₃. In an embodiment, when R² is Cl,R³ is Me, R⁴ is Me, Et, cyclohexyl, cyclopentyl or n-Butyl, R⁵ is H, R⁶is H and n is 1, then R¹ is not Cl.

In an embodiment, when R³ is Me, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R¹ is not F, Cl, Br, I, —CH₃ or —CF₃.

In an embodiment, when R¹ is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 0,then R³ is not Et, n-propyl or isopropyl. In an embodiment, when R¹ isBr, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is not cyclopropyl,1,1-difluoroethan-2-yl, 1-methoxypropan-2-yl or 1-ethoxycyclobutan-3-yl.

In one aspect, the invention relates to a compound of Formula (III.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, I, and -oxime optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;            or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof, for use in treating,            ameliorating and/or preventing a neuromuscular disorder,            and/or for use in reversing and/or ameliorating a            neuromuscular blockade.

In one aspect, the invention relates to a compound of Formula (IV.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, and I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;            or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof, for use in treating,            ameliorating and/or preventing a neuromuscular disorder,            and/or for use in reversing and/or ameliorating a            neuromuscular blockade.

In one aspect, the invention relates to a compound of Formula (V.2):

-   -   wherein:        -   R¹ is Br, Cl or I;        -   R² is independently deuterium, F, Cl, Br, or I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;            or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof, for use in treating,            ameliorating and/or preventing a neuromuscular disorder,            and/or for use in reversing and/or ameliorating a            neuromuscular blockade.

In one aspect, the invention relates to a compound of Formula (VI.2):

-   -   wherein:        -   R¹ is Br, Cl or I;        -   R² is independently deuterium, F, Cl, Br, or I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;            or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof, for use in treating,            ameliorating and/or preventing a neuromuscular disorder,            and/or for use in reversing and/or ameliorating a            neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2):

wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R² is independently selected from the group consisting of        hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime        optionally substituted with C₁ alkyl;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of Cl and Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl        optionally substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, C₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which is substituted with one or more, identical or        different, substituents R⁵; and    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₃₋₅ cycloalkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl and C₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R₅;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one aspect, the invention relates to an embodiment of the compound ofFormula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I, —CN, —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl,        C₃₋₄ cycloalkyl and —S—CH₃;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br and I;    -   R³ is selected from the group consisting of fluoromethyl,        fluoroethyl and fluoropropyl, each of which may be optionally        substituted with one or more deuterium;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one embodiment, R¹ is selected from the group consisting of F, Cl,Br, and I, such as R¹ is selected from the group consisting of Cl andBr. In one embodiment, R¹ is Br.

In one embodiment, R² is selected from the group consisting ofdeuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime optionally substitutedwith C₁ alkyl. In one embodiment, R² is selected from the groupconsisting of F, Cl and Br. In one embodiment, R² is deuterium or F,such as deuterium. In one embodiment, R² is hydrogen or deuterium. Inanother embodiment, R² is an oxime, such as an aldoxime. Said oxime maybe substituted with C₁ alkyl.

In some embodiments, R¹ is different from R², such as R¹ is Cl and R² isF; R¹ is Cl and R² is Br; such as R¹ is Cl and R² is H; such as R¹ is Cland R² is D; such as R¹ is Br and R² is F; such as R¹ is Br and R² isCl; such as R¹ is Br and R² is H; such as R¹ is Br and R² is D.

In some embodiments, R¹ and R² are the same, such as R¹ is Cl and R² isCl or such as R¹ is Br and R² is Br.

In one embodiment, R³ is selected from the group consisting of C₁₋₃alkyl and C₃₋₄ cycloalkyl optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R³ isselected from the group consisting of C₁₋₃ alkyl and C₃₋₄ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁵, with the proviso that when R¹ is Cl, R² is Cl, R⁴ is H,R⁶ is H, n is 0 and R³ is ethyl, then said ethyl is substituted with oneor more, identical or different, substituents R⁵. In one embodiment,said C₁₋₃ alkyl is methyl.

In one embodiment, R³ is selected from the group consisting of C₂₋₃alkyl and C₃₋₄ cycloalkyl optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R³ isselected from the group consisting of C₂₋₃ alkyl and C₃₋₄ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁵, with the proviso that when R¹ is Cl, R² is Cl, R⁴ is H,R⁶ is H, n is 0 and R³ is ethyl, then said ethyl is substituted with oneor more, identical or different, substituents R⁵.

In one embodiment, R³ is selected from the group consisting of methyl,ethyl, n-propyl or isopropyl optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R³ is methylsubstituted with one or more, identical or different, substituents R⁵;such as R³ is methyl. In one embodiment, R³ is ethyl optionallysubstituted with one or more, identical or different, substituents R⁵with the proviso that when R¹ is Cl, R² is Cl, R⁴ is H, R⁶ is H, n is 0,and R³ is ethyl, then said ethyl is substituted with one or more,identical or different, substituents R⁵; such as R³ is ethyl.

In one embodiment, R³ is n-propyl optionally substituted with one ormore, identical or different, substituents R⁵. In one embodiment, R³ isisopropyl optionally substituted with one or more, identical ordifferent, substituents R⁵. In one embodiment, R³ is n-propyl orisopropyl.

In one embodiment, R³ is C₁₋₅ alkyl substituted with one or more F.Thus, in one embodiment, R³ is selected from the group consisting offluoromethyl, fluoroethyl and fluoropropyl. In one embodiment, R³ isselected from the group consisting of —CH₂F, —CHF₂, —CF₃, —CH₂CH₂F,—CH₂CHF₂ and —CH₂CF₃, preferably —CH₂F. In one embodiment, R³ isselected from the group consisting of fluoromethyl, difluoromethyl,2-fluoroeth-1-yl, (1S)-1-fluoroeth-1-yl, (1R)-1-fluoroeth-1-yl,(1S)-1,2-difluoroeth-1-yl, (1R)-1,2-difluoroeth-1-yl, 3-fluoroprop-1-yl,(1S)-1-fluoroprop-1-yl, (1R)-1-fluoroprop-1-yl, (2S)-2-fluoroprop-1-yl,(2R)-2-fluoroprop-1-yl, (1S)-2-fluoro-1-methyl-eth-1-yl,(1S)-2-fluoro-1-methyl-eth-1-yl and 2-fluoro-1-(fluoromethyl)eth-1-yl.In one embodiment, R³ is selected from the group consisting offluoromethyl, 2-fluoroeth-1-yl, (1S)-1-fluoroeth-1-yl and(1R)-1-fluoroeth-1-yl.

In one embodiment, R³ is cyclopropyl optionally substituted with one ormore, identical or different, substituents R⁵. In one embodiment, R³ iscyclopropylmethyl optionally substituted with one or more, identical ordifferent, substituents R⁵. In one embodiment, R³ is cyclobutyloptionally substituted with one or more, identical or different,substituents R⁵.

In one embodiment, R³ is C₃₋₅ cycloalkyl, optionally substituted withone or more F. Thus, in one embodiment, R³ is selected from the groupconsisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl and cyclobutylmethyl, optionally substituted with oneor more F.

In one embodiment, R³ is C₂₋₅ alkenyl, optionally substituted with oneor more, identical or different, substituents R⁵. In one embodiment,said C₂₋₅ alkenyl is a cycloalkenyl. In one embodiment, R³ is selectedfrom the group consisting of ethenyl, propenyl, isopropenyl, butenyl,isobutenyl and pentenyl, optionally substituted with one or more F.

In one embodiment, R³ is optionally substituted with one or more,identical or different, substituents R⁵. In one embodiment, R⁵ isindependently selected from the group consisting of deuterium, F, —OC₁₋₅alkyl optionally substituted with one or more, identical or different,substituents R⁷ and —OC₃₋₅ cycloalkyl optionally substituted with one ormore, identical or different, substituents R⁷.

In one embodiment, R⁵ is independently deuterium or F. In oneembodiment, R³ is substituted with one or more deuterium, such as R³ isselected from the group consisting of trideuteriomethyl,1,2-dideuterioethyl and 1,1,2,2-tetradeuterioethyl.

In one embodiment, R³ is substituted with one fluorine.

In one embodiment, R³ is substituted with one or more —OC₁₋₅ alkylgroups optionally substituted with one or more, identical or different,substituents R⁷; such as R³ is substituted with one or more —OMe groupsoptionally substituted with one or more, identical or different,substituents R⁷; such as R³ is substituted with one or more —OEt groupsoptionally substituted with one or more, identical or different,substituents R⁷; or such as R³ is substituted with one or more —OC₃₋₅cycloalkyl groups optionally substituted with one or more, identical ordifferent, substituents R⁷.

In one embodiment, R⁴ is H forming an acid. In one embodiment, said acidis deprotonated. Said deprotonated acid may interact with a cation, suchas an alkali metal cation. In one embodiment, R⁴ is the sodiumcounterion.

In one embodiment, R⁶ is H. In another embodiment, R⁶ is D.

In one embodiment, n is an integer 0, 1, 2, 3, or 4, such as n is 0;such as n is 1; such as n is 2.

In one embodiment,

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which may        be optionally substituted with one or more F; and    -   R⁴ is selected from the group consisting of H and Ci-s alkyl,        preferably H;    -   n is 0;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof, for use in treating, ameliorating        and/or preventing a neuromuscular disorder, and/or for use in        reversing and/or ameliorating a neuromuscular blockade.

In one embodiment,

-   -   R¹ is Cl;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, O₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

In one embodiment,

-   -   R¹ is Cl;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0.

In one embodiment,

-   -   R¹ is Cl;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

In one embodiment,

-   -   R¹ is Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, C₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

In one embodiment,

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0.

In one embodiment,

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and        n is 0, 1, 2 or 3.

In one aspect, the invention relates to the use of compounds of Formula(VII.2) in treating, ameliorating and/or preventing a neuromusculardisorder. In one aspect, the invention relates to the use of compoundsof Formula (VII.2) in reversing and/or ameliorating a neuromuscularblockade.

In one embodiment, the compound for use in treating, ameliorating and/orpreventing a neuromuscular disorder, and/or for use in reversing and/orameliorating a neuromuscular blockade is selected from the groupconsisting of:

In one embodiment, the compound for use in treating, ameliorating and/orpreventing a neuromuscular disorder, and/or for use in reversing and/orameliorating a neuromuscular blockade is selected from the groupconsisting of:

-   (2R)-2-[4-bromo(3,5-²H₂)phenoxy]-3-fluoropropanoic acid;-   (2S)-2-[4-bromo(3,5-²H₂)phenoxy]propanoic acid;-   ethyl (2S)-2-(4-bromo-2-fluorophenoxy)-3-methylbut-3-enoate;-   (2R)-2-[4-bromo(2,6-²H₂)phenoxy]-3-fluoropropanoic acid;-   (2S)-2-[4-bromo(2,6-²H₂)phenoxy]propanoic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)propanoic acid;-   (2R)-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropanoic acid;-   (2S)-2-{4-bromo-2-[(1E)-(methoxyimino)methyl]phenoxy}propanoic acid;-   (2S)-2-(2-bromo-4-chlorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(2-fluoro-4-iodophenoxy)propanoic acid;-   (2S)-2-(2-bromo-4-iodophenoxy)propanoic acid;-   ethyl 2-(4-bromo-2-fluorophenoxy)-3,3,3-trifluoropropanoate;-   ethyl 2-(4-bromophenoxy)-3,3,3-trifluoropropanoate;-   (2S)-2-(2-chloro-4-iodophenoxy)propanoic acid;-   (2S)-2-(2-bromo-4-chlorophenoxy)propanoic acid;-   2-(4-bromophenoxy)-2-cyclopentylacetic acid;-   (2R)-2-(4-bromo-2-fluorophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-chloro-2-fluorophenoxy)-3-methylbutanoic acid;-   (2R)-2-(2-bromo-4-chlorophenoxy)-3-fluoropropanoic acid;-   (2R)-2-(4-chlorophenoxy)-3-fluoropropanoic acid;-   (2R)-2-(4-chloro-2-fluorophenoxy)-3-fluoropropanoic acid;-   (2R)-2-(2,4-dibromophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-bromophenoxy)-3-hydroxypropanoic acid;-   (2R)-2-(4-bromophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(3-bromo-4-chlorophenoxy)propanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)propanoic acid;-   (2 S)-2-[4-(trifluoromethyl)phenoxy]propanoic acid;-   sodium (2S)-2-(4-chlorophenoxy)-5-methylhexanoate;-   methyl (2S)-2-(4-chlorophenoxy)-5-methylhexanoate;-   sodium (2S)-2-(4-chlorophenoxy)-4-methylpentanoate;-   sodium (2S)-2-(4-chlorophenoxy)hexanoic acid;-   methyl (2S)-2-(4-chlorophenoxy)hexanoate;-   (2S)-2-(4-chloro-2-fluorophenoxy)propanoic acid;-   (2S)-2-(3,4-dichlorophenoxy)propanoic acid;-   (2S)-2-(2,4-dibromophenoxy)propanoic acid;-   (2S)-2-[4-(prop-1-yn-1-yl)phenoxy]propanoic acid;-   (2S)-2-(4-ethynylphenoxy)propanoic acid;-   sodium (2S)-2-(4-chlorophenoxy)butanoate;-   sodium (2S)-2-(2,4-dichlorophenoxy)propanoate;-   sodium (2S)-2-(4-chlorophenoxy)-3-methylbutanoate;-   sodium (2S)-2-(4-ethylphenoxy)propanoate;-   sodium (2S)-2-(4-cyanophenoxy)propanoate;-   sodium (2S)-2-[4-(methylsulfanyl)phenoxy]propanoate;-   methyl (2S)-2-(4-ethynylphenoxy)propanoate;-   methyl (2S)-2-(4-bromophenoxy)propanoate;-   methyl (2S)-2-(4-chlorophenoxy)butanoate;-   2,2,2-trifluoroethyl (2S)-2-(4-chlorophenoxy)propanoate;-   propan-2-yl (2S)-2-(4-chlorophenoxy)propanoate;-   methyl (2S)-2-(4-chlorophenoxy)propanoate;-   (2S)-2-(4-bromo-2,6-difluorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(4-bromophenoxy)butanoic acid;-   (2S)-2-(4-cyclobutylphenoxy)propanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)butanoic acid;-   (2S,3E)-2-(4-bromophenoxy)-4-fluorobut-3-enoic acid;-   (2S)-2-(4-bromophenoxy)(2-²H)butanoic acid;-   (2S)-2-(4-bromophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)pentanoic acid;-   (2S)-2-(2,4-dibromophenoxy)pentanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)pentanoic acid;-   (2S)-2-(4-bromophenoxy)-3-cyclopropylpropanoic acid;-   (2S)-2-(2,4-dibromophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromophenoxy)-2-cyclopropylacetic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromophenoxy)pentanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-2-cyclobutylacetic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-3-cyclopropylpropanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(2,4-dibromophenoxy)-3-methoxypropanoic acid;-   (2S)-2-(4-bromophenoxy)but-3-enoic acid;-   (2S)-2-(4-bromophenoxy)(3,4-²H₂)butanoic acid;-   (2R)-2-(4-bromo-2-chlorophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)butanoic acid;-   (2S)-2-(4-bromo-3-fluorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromo-2,3-difluorophenoxy)-3-methylbutanoic acid;-   (2R)-2-(4-bromophenoxy)-3-fluoro(2-²H)propanoic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromophenoxy)-2-cyclobutylacetic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-2-cyclobutylacetic acid;-   (2S)-2-(4-bromophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)-3-methylbutanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-2-cyclopropylacetic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)butanoic acid;-   (2S)-2-(4-chloro-2-fluorophenoxy)butanoic acid;-   (2S)-2-cyclopropyl-2-(2,4-dibromophenoxy)acetic acid,-   (2S)-2-(4-bromo-2-chlorophenoxy)-2-cyclopropylacetic acid,-   (2R,3R)-2-(4-bromophenoxy)-3-fluorobutanoic acid, and-   (2R,3R)-2-(4-bromo-2-fluorophenoxy)-3-fluorobutanoic acid.

In one embodiment, the compound or the compound for use according to thepresent invention has been modified in order to increase its half-lifewhen administered to a patient, in particular its plasma half-life.

In one embodiment, the compound or the compound for use according to thepresent invention further comprises a moiety conjugated to saidcompound, thus generating a moiety-conjugated compound. In oneembodiment, said moiety-conjugated compound has a plasma and/or serumhalf-life being longer than the plasma and/or serum half-life of thenon-moiety conjugated compound.

In one embodiment, the moiety conjugated to the compound or compound foruse according to the present invention, is one or more type(s) ofmoieties selected from the group consisting of albumin, fatty acids,polyethylene glycol (PEG), acylation groups, antibodies and antibodyfragments.

Another aspect of the invention relates to a method of reversing and/orameliorating a neuromuscular blockade after surgery, said methodcomprising administering a therapeutically effective amount of thecomposition as defined in any one of the embodiments herein below to aperson in need thereof.

In yet another aspect, the present invention relates to use of acomposition as defined herein, for the manufacture of a medicament forreversing and/or amelioration of a neuromuscular blockade after surgery.

Combination Therapy

The composition of the present invention may comprise further activeingredients/agents or other components to increase the efficiency of thecomposition. Thus, in one embodiment the composition further comprisesat least one further active agent. It is appreciated that the activeagent is suitable for treating, preventing or ameliorating saidneuromuscular disorder.

The active agent is in a preferred embodiment an acetylcholine esteraseinhibitor. Said acetylcholine esterase inhibitor may for example beselected from the group consisting of delta-9-tetrahydrocannabinol,carbamates, physostigmine, neostigmine, pyridostigmine, ambenonium,demecarium, rivastigmine, phenanthrene derivatives, galantamine,caffeine-noncompetitive, piperidines, donepezil, tacrine, edrophonium,huperzine, ladostigil, ungeremine and lactucopicrin.

Preferably the acetylcholine esterase inhibitor is selected from thegroup consisting of neostigmine, physostigmine and pyridostigmine. It ispreferred that the acetylcholine esterase inhibitor is neostigmine orpyridostigmine.

The active agent may also be an immunosuppressive drug.limmunosuppressive drugs are drugs that suppress or reduce the strengthof the body's immune system. They are also known as anti-rejectiondrugs. Immunosuppressive drugs include but are not limited toglucocorticoids, corticosteroids, cytostatics, antibodies and drugsacting on immunophilins. In one embodiment the active agent isprednisone.

The active agent may also be an agent that is used in anti-myotonictreatment. Such agents include for example blockers of voltage gated Na⁺channels, and aminoglycosides.

The active agent may also be an agent for reversing a neuromuscularblockade after surgery. Such agents include for example neostigmine orsuggammadex.

The active agent may also be an agent for increasing the Ca²⁺sensitivity of the contractile filaments in muscle. Such agent includestirasemtiv.

The active agent may also be an agent for increasing ACh release byblocking voltage gated K⁺ channels in the pre-synaptic terminal. Suchagent includes 3,4-aminopyridine. As illustrated in example 5,combination therapy using C8 and 3,4-diaminopyridine resulted in anunexpected synergistic effect on recovery of neuromuscular transmission.

Pharmaceutical Formulations

In one embodiment, a composition comprising the compound or the compoundfor use, according to the present invention, is provided. Thecomposition according to the present invention is used for treating,ameliorating and/or preventing a neuromuscular disorder, and/or for usein reversing and/or ameliorating a neuromuscular blockade. Thus, it ispreferred that the compositions and compounds described herein arepharmaceutically acceptable. In one embodiment the composition asdescribed herein is in the form of a pharmaceutical formulation. In oneembodiment, the composition as described herein further comprises apharmaceutically acceptable carrier. Accordingly, the present inventionfurther provides a pharmaceutical formulation, which comprises acompound of as disclosed herein and a pharmaceutically acceptable saltor a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof, as herein defined, and a pharmaceutically acceptable carrier.Thus, in one embodiment the composition of the present invention furthercomprises a pharmaceutically acceptable carrier. The pharmaceuticalformulations may be prepared by conventional techniques, e.g. asdescribed in Remington: The Science and Practice of Pharmacy 2005,Lippincott, Williams & Wilkins.

The pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier can beone or more excipients which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,wetting agents, tablet disintegrating agents, or an encapsulatingmaterial.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The compositions of the present invention may be formulated forparenteral administration and may be presented in unit dose form inampoules, pre-filled syringes, small volume infusion or in multi-dosecontainers, optionally with an added preservative. The compositions maytake such forms as suspensions, solutions, or emulsions in oily oraqueous vehicles, for example solutions in aqueous polyethylene glycol.Examples of oily or non-aqueous carriers, diluents, solvents or vehiclesinclude propylene glycol, polyethylene glycol, vegetable oils (e.g.,olive oil), and injectable organic esters (e.g., ethyl oleate), and maycontain agents such as preserving, wetting, emulsifying or suspending,stabilizing and/or dispersing agents. Alternatively, the activeingredient may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution for constitution beforeuse with a suitable vehicle, e.g., sterile, pyrogen-free water.

In a preferred embodiment the compositions of the present invention isformulated for oral administration. Oral administration forms includesolid form preparations including powders, tablets, drops, capsules,cachets, lozenges, and dispersible granules. Other forms suitable fororal administration may include liquid form preparations includingemulsions, syrups, elixirs, aqueous solutions, aqueous suspensions,toothpaste, gel dentrifrice, chewing gum, or solid form preparationswhich are intended to be converted shortly before use to liquid formpreparations, such as solutions, suspensions, and emulsions. In powders,the carrier is a finely divided solid which is a mixture with the finelydivided active component.

In a preferred embodiment the composition as described herein isformulated in a tablet or capsule. In tablets, the active component ismixed with the carrier having the necessary binding capacity in suitableproportions and compacted in the shape and size desired. Suitablecarriers are magnesium carbonate, magnesium stearate, talc, sugar,lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose,sodium carboxymethylcellulose, a low melting wax, cocoa butter, and thelike.

Drops according to the present invention may comprise sterile ornon-sterile aqueous or oil solutions or suspensions, and may be preparedby dissolving the active ingredient in a suitable aqueous solution,optionally including a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and optionally including a surface activeagent. Suitable solvents for the preparation of an oily solution includeglycerol, diluted alcohol and propylene glycol.

Emulsions may be prepared in solutions in aqueous propylene glycolsolutions or may contain emulsifying agents such as lecithin, sorbitanmonooleate, or acacia. Aqueous solutions can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents. Aqueous suspensions can be preparedby dispersing the finely divided active component in water with viscousmaterial, such as natural or synthetic gums, resins, methylcellulose,sodium carboxymethylcellulose, and other well-known suspending agents.

The compositions of the present invention may also be formulated in awide variety of formulations for parenteral administration.

For injections and infusions the formulations may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Alternatively, thecomposition may be in powder form, obtained by aseptic isolation ofsterile solid or by lyophilisation from solution for constitution beforeuse with a suitable vehicle, e.g., sterile, pyrogen-free water. Theformulations can be presented in unit-dose or multi-dose sealedcontainers, such as ampoules, vials, pre-filled syringes, infusion bags,or can be stored in a freeze-dried (lyophilized) condition requiringonly the addition of the sterile liquid excipient, for example, water,for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions can be prepared from sterile powders,granules, and tablets.

Examples of oily or non-aqueous carriers, diluents, solvents or vehiclesinclude propylene glycol, polyethylene glycol, vegetable oils, andinjectable organic esters, and may contain formulatory agents such aspreserving, wetting, emulsifying or suspending, stabilizing and/ordispersing agents.

The formulations for injection will typically contain from about 0.5 toabout 25% by weight of the active ingredient in solution.

Topical Delivery

The compounds may also be administered topically. Regions for topicaladministration include the skin surface and also mucous membrane tissuesof the vagina, rectum, nose, mouth, and throat.

The topical composition will typically include a pharmaceuticallyacceptable carrier adapted for topical administration. Thus, thecomposition may take the form of a suspension, solution, ointment,lotion, sexual lubricant, cream, foam, aerosol, spray, suppository,implant, inhalant, tablet, capsule, dry powder, syrup, balm or lozenge,for example. Methods for preparing such compositions are well known inthe pharmaceutical industry.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. They may be made by mixing the active ingredient infinely-divided or powdered form, alone or in solution or suspension inan aqueous or non-aqueous fluid, with the aid of suitable machinery,with a greasy or non-greasy base. The base may comprise hydrocarbonssuch as hard, soft or liquid paraffin, glycerol, beeswax, a metallicsoap; a mucilage; an oil of natural origin or a fatty acid. Theformulation may incorporate any suitable surface active agent such as ananionic, cationic or non-ionic surfactant such as a sorbitan ester or apolyoxyethylene derivative thereof. Suspending agents such as naturalgums, cellulose derivatives or inorganic materials such as silicaceoussilicas, and other ingredients such as lanolin, may also be included.

Lotions according to the present invention also include those suitablefor application to the eye. An eye lotion may comprise a sterile aqueoussolution optionally containing a bactericide.

Nasal, Pulmonary and Bronchial Administration

Formulations for use in nasal, pulmonary and/or bronchial administrationare normally administered as aerosols in order to ensure that theaerosolized dose actually reaches the mucous membranes of the nasalpassages, bronchial tract or the lung. The term “aerosol particle” isused herein to describe the liquid or solid particle suitable for nasal,bronchial or pulmonary administration, i.e., that will reach the mucousmembranes.

Typically aerosols are administered by use of a mechanical devicesdesigned for pulmonary and/or bronchial delivery, including but notlimited to nebulizers, metered dose inhalers, and powder inhalers. Withregard to construction of the delivery device, any form ofaerosolization known in the art, including but not limited to spraybottles, nebulization, atomization or pump aerosolization of a liquidformulation, and aerosolization of a dry powder formulation, can beused.

Liquid Aerosol Formulations in general contain a compound of the presentinvention in a pharmaceutically acceptable diluent. Pharmaceuticallyacceptable diluents include but are not limited to sterile water,saline, buffered saline, dextrose solution, and the like.

Formulations for dispensing from a powder inhaler device will normallycomprise a finely divided dry powder containing pharmaceuticalcomposition of the present invention (or derivative) and may alsoinclude a bulking agent, such as lactose, sorbitol, sucrose, or mannitolin amounts which facilitate dispersal of the powder from the device. Drypowder formulations for inhalation may also be formulated usingpowder-filled capsules, in particularly capsules the material of whichis selected from among the synthetic plastics.

The formulation is formulated to the type of device employed and mayinvolve the use of an appropriate propellant material, in addition tothe usual diluents, adjuvants and/or carriers useful in therapy andknown to the person skilled in the art. The propellant may be anypropellant generally used in the art. Specific non-limiting examples ofsuch useful propellants are a chlorofluorocarbon, a hydrofluorocarbon, ahydrochlorofluorocarbon, or a hydrocarbon.

The formulations of the present embodiment may also include other agentsuseful for pH maintenance, solution stabilization, or for the regulationof osmotic pressure.

The formulations of the present embodiment may also include other agentsuseful for pH maintenance, solution stabilization, or for the regulationof osmotic pressure.

Transdermal Delivery

The pharmaceutical agent-chemical modifier complexes described hereincan be administered transdermally. Transdermal administration typicallyinvolves the delivery of a pharmaceutical agent for percutaneous passageof the drug into the systemic circulation of the patient. The skin sitesinclude anatomic regions for transdermally administering the drug andinclude the forearm, abdomen, chest, back, buttock, mastoidal area, andthe like.

Transdermal delivery is accomplished by exposing a source of the complexto a patient's skin for an extended period of time. Transdermal patcheshave the added advantage of providing controlled delivery of apharmaceutical agent-chemical modifier complex to the body. Such dosageforms can be made by dissolving, dispersing, or otherwise incorporatingthe pharmaceutical agent-chemical modifier complex in a proper medium,such as an elastomeric matrix material. Absorption enhancers can also beused to increase the flux of the compound across the skin. The rate ofsuch flux can be controlled by either providing a rate-controllingmembrane or dispersing the compound in a polymer matrix or gel. Forexample, a simple adhesive patch can be prepared from a backing materialand an acrylate adhesive.

Administration Forms

As described herein above administration forms include but are notlimited to oral, parental, topical, enteral, rectal or buccaladministration.

In one embodiment the composition is administered or adapted foradministration enterally, topically, parenterally or as part of asustained release implant. The parenteral administration may for examplebe intravenous, subcutaneous, intramuscular, intracranial orintraperitoneal. In a preferred embodiment the parental administrationis intramuscular. Enteral administration includes oral, rectal, orbuccal administration. In one embodiment topical administration isdermal, epicutaneous, vaginal, intravesical, pulmonary, intranasal,intratracheal or as eye drops.

In another embodiment the composition is administered or adapted foradministration subcutaneously or intravenously.

It is appreciated that the composition of the present inventioncomprises at least 30 wt. % compound, such as at least 25 wt. %compound, such as for example at least 20 wt. % compound, at least 15wt. % compound, such as at least 25 wt. % compound, such as for exampleat least 20 wt. % compound, at least 15 wt. % compound, such as at least10 wt. % compound, such as for example at least 8 wt. % compound, atleast 5 wt. % compound, such as at least 4 wt. % compound, such as forexample at least 3 wt. % compound, at least 2 wt. % compound, such as atleast 1 wt. % compound, such as for example at least 0.5 wt. % compoundor at least 0.5 wt. % compound. Wt. % is an abbreviation for weightpercent.

The compound is any compound defined by Formula (I). Thus, the activeingredient can be any of the compounds defined by the formulas orembodiments presented herein.

In one embodiment the compound as described herein is to be administeredin a dosage of from 1 μg/kg-30,000 μg/kg body weight, such as 1μg/kg-7,500 μg/kg, such as 1 μg/kg-5,000 μg/kg, such as 1 μg/kg-2,000μg/kg, such as 1 μg/kg-1,000 μg/kg, such as 1 μg/kg-700 μg/kg, such as 5μg/kg-500 μg/kg, such as 10 μg/kg to 100 μg/kg bodyweight.

In another embodiment the compound as described herein is to beadministered in a dosage of from 1 μg/kg-1,000 μg/kg body weight, suchas 1 μg/kg-500 μg/kg, such as 1 μg/kg-250 μg/kg, such as 1 μg/kg-100μg/kg, such as 1 μg/kg-50 μg/kg, such as 1 μg/kg to 10 μg/kg bodyweight.

In yet another embodiment the compound as described herein is to beadministered in a dosage of from 10 μg/kg-30,000 μg/kg body weight, suchas 10 μg/kg-7,500 μg/kg, such as 10 μg/kg-5,000 μg/kg, such as 10μg/kg-2,000 μg/kg, such as 10 μg/kg-1,000 μg/kg, such as 10 μg/kg-700μg/kg, such as 10 μg/kg-500 μg/kg, such as 10 μg/kg to 100 μg/kgbodyweight.

In one embodiment the administration of the composition as describedherein is repeated at least 1, 2, 3, 4, 5 or 6 times weekly.

In another embodiment the administration is repeated at least 1-3 timesweekly, such as 2-5 times weekly, such as 3-6 times weekly.

In a further embodiment the administration is repeated daily. Theadministration of the composition may for example be repeated 1, 2, 3,4, 5, 6, 7 or 8 times daily. In one embodiment the administration isrepeated 1 to 8 times daily, such as 2 to 5 times daily.

The compound as defined herein can be modified in order to increase itshalf-life when administered to a patient, in particular its plasmahalf-life.

The term “half-life” as used herein is the time it takes for thecompound to lose one-half of its pharmacologic activity. The term“plasma half-life” is the time that it takes the compound to loseone-half of its pharmacologic activity in the blood plasma.

Modification of the compound to increase its half-life may for exampleinclude conjugation of a moiety that increases the half-life of thecompound. Thus, in an embodiment the compound further comprises a moietyconjugated to said compound, thus generating a moiety-conjugatedcompound. It is preferred that the moiety-conjugated compound has aplasma and/or serum half-life being longer than the plasma and/or serumhalf-life of the non-moiety conjugated compound.

The moiety conjugated to the compound can for example be one or moretype(s) of moieties selected from the group consisting of albumin, fattyacids, polyethylene glycol (PEG), acylation groups, antibodies andantibody fragments.

Methods

In one aspect the present invention relates to a method of treating,preventing and/or ameliorating a neuromuscular disorder, said methodcomprising administering a therapeutically effective amount of thecompositions and compounds as defined herein to a person in needthereof.

In one aspect, the present invention relates to a method of reversingand/or ameliorating a neuromuscular blockade, said method comprisingadministering a therapeutically effective amount of the compound or thecompound for use as defined herein to a person in need thereof.

In one aspect, the present invention relates to a method for recovery ofneuromuscular transmission, said method comprising administering atherapeutically effective amount of the compound or the compound for useas defined herein to a person in need thereof.

The person in need thereof may be a person having a neuromusculardisorder or a person at risk of developing a neuromuscular disorder or aperson having symptoms of muscle weakness and/or fatigue. In anotherembodiment the person in need thereof is a person with reducedneuromuscular transmission safety with prolonged recovery afterneuromuscular blockade. Types of neuromuscular disorders are definedherein above. In a preferred embodiment the person has, amyotrophiclateral sclerosis, spinal muscular atrophy, myasthenia gravis orLambert-Eaton syndrome.

A therapeutically effective amount is an amount that produces atherapeutic response or desired effect in the person taking it.Administration routes, formulations, forms and dosages are as definedherein above and throughout this specification.

The method of treatment may be combined with other methods that areknown to treat, prevent and/or ameliorate neuromuscular disorders. Thetreatment method may for example be combined with administration of anyof the agents mentioned herein above. In one embodiment the treatment iscombined with administration of acetylcholine esterase inhibitor such asfor example neostigmine or pyridostigmine.

Another aspect of the invention relates to use of a composition asdefined herein, for the manufacture of a medicament for the treatment,prevention and/or amelioration of a neuromuscular disorder.

Another aspect relates to use of a composition as defined herein, forthe manufacture of a medicament or a reversal agent for reversing and/orameliorating a neuromuscular blockade after surgery.

Method of Manufacturing

In one aspect, the present invention relates to methods of manufacturingcompounds or compounds for use according to formula (I).

One method for manufacturing the compounds or compounds for useaccording to the present invention comprises the steps of

-   -   a. reacting a compound having formula (VIII)

-   -   wherein R³ is as defined herein and R⁶ is a protecting group,        such as selected from the group consisting of alkyl, alkenyl,        akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic        ring and -alkylene-Si-alkyl, with first a reagent capable of        converting the alcohol (OH) into a leaving group and secondly        with a compound having formula (VII)

-   -   wherein R¹, R², and n are as defined herein and Y is O to        generate a compound having formula (IX)

and

-   -   b. reacting the product compound of a) with an ester hydrolysing        reagent thus generating a compound as defined herein.

A second method for manufacturing the compounds or compounds for useaccording to the present invention comprises the steps of

-   -   a. reacting a compound having formula (XI)

-   -   wherein R¹, R² and n are as defined herein and Q is a leaving        group, such as selected from the group consisting of fluorine        and iodine, with a compound having formula (XII)

-   -   wherein R³ is as defined herein, and R⁶ is a protecting group,        such as selected from the group consisting of alkyl, alkenyl,        akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic        ring and -alkylene-Si-alkyl to generate a compound having        formula (X)

-   -   wherein Y is O; and    -   b. reacting the product compound of a) with an ester hydrolysing        reagent thus generating a compound as defined herein.

Yet a third method for manufacturing the compounds or compounds for useaccording to the present invention comprises the steps of

-   -   a. reacting a compound having formula (XIII)

-   -   wherein R³ is as defined herein, Z is OH and R⁷ is a protecting        group, such as an —Si-alkyl, with first a reagent capable of        converting the alcohol (Z) into a leaving group and secondly        with a compound having formula (VII)

-   -   wherein R¹, R² and n are as defined herein, and Y is O to        generate a compound having formula (XIV)

-   -   b. reacting the product compound of a) with an ether cleaving        reagent to generate a compound having formula (XV)

and

-   -   c. reacting the product compound of b) with an oxidising agent        thus generating a compound as defined herein.

Prodrugs

The compounds of formula (I) may be administered as a prodrug to modifythe distribution, duration of efficacy or other properties. Conversionof the carboxylic acid group of compounds of formula (I) to an esterusing ethanol to form the ethyl ester is an example of such prodrug.Preferred alcohols include low molecular weight alcohols, phenols andother aromatic alcohols, and fluorinated alcohols. In some cases, it ispreferable to use an enol as the alcohol, for example4-hydroxy-pent-3-ene-2-one. Alternatively, the prodrug may be thecorresponding aldehyde, or an imine thereof. Again, these precursors canbe expected to transform to the carboxylic acid in vivo. The prodrugsare administered using the same formulations and in the same dosageranges as the compounds of formula (I).

In one aspect, said prodrug is defined by Formula (LX):

or a salt of tautomer thereofwherein m, A, Z, R₁, R₂ and R₄ are as defined above and wherein R₁₄ isan aromatic or heteroaromatic ring selected from the group consisting ofphenyl, pyrimidyl, pyridinyl, thiazolyl, oxadiazolyl and quinolyl, allaromatic and heteroaromatic groups optionally substituted by one or moreR₄

In one embodiment R₁₄ is a phenyl substituted with methoxy, nitro,cyano, Cl, Br, I and/or F.

In one embodiment Formula (LX) is further defined by Formula (LXI):

In another embodiment of the present invention the prodrug is defined byFormula (LXII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof, wherein m, A, Z, R₁, R₂ and R₄ are as defined above.

The prodrug can also be defined by Formula (LXIII):

wherein m, A, Z, R₁, R₂ and R₄ are as defined above, and B is a 5- to7-membered heterocyclic.

EMBODIMENTS OF THE INVENTION

Embodiment 1 is a composition comprising a compound of Formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂; wherein        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl    -   for use in treating, ameliorating and/or preventing a        neuromuscular disorder.

Embodiment 2 is a composition according to embodiment 1, wherein A is amonocyclic or bicyclic aromatic or heteroaromatic ring.

Embodiment 3 composition according to embodiments 1 and 2, wherein A isfive-membered or six-membered aromatic ring.

Embodiment 4 composition according to embodiment 1 to 3, wherein A isphenyl, or naphthyl.

Embodiment 5 composition according to any of the preceding embodiments,wherein said compound is a compound of Formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof;    -   wherein        -   m is 0, 1, 2, 3, 4 or 5;        -   Y is selected from the group consisting of O, NH, N—CHs,            CH₂, CH₂—O, S and SO₂;        -   X₁, X₂ and X₃ are independently selected from the group            consisting of CH and N;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a C₃₋₆-cycloalk(en)yl or a            halo-C₃₋₆-cycloalk(en)yl;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R⁵ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃, nitro and halo; or R₁ and            R₂ are linked to form a ring;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl;        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl;    -   for use in treating, ameliorating and/or preventing a        neuromuscular disorder.

Embodiment 6 is a composition for use according to any one of thepreceding embodiments, wherein R₁ is selected from the group consistingof H and —CH₃.

Embodiment 7 is a composition according to any one of the precedingembodiments, wherein R₁ is H.

Embodiment 8 is a composition for use according to any of the precedingembodiments, wherein R₁ is H and R₂ is selected from the groupconsisting of H, C₁₋₄-alk(en)yl, C₃₋₆-cycloalk(en)yl, wherein saidC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted with up totwo substituents selected from the group consisting of —NR₉—CO—R₁₀,—N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀,—S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro andhalo, wherein R₉, R₁₀, and R₁₁ are independently selected from H,C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, whereas R₁₂ is selected fromC₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl.

Embodiment 9 is a composition for use according to any of the precedingembodiments, wherein R₁ is H and R₂ is selected from the groupconsisting of H, C₁₋₄-alkyl, C₃₋₆-cycloalkyl and amino-C₁₋₄-alkyl,wherein said C₁₋₄-alkyl and C₃₋₆-cycloalkyl may be substituted withO—R₁₁, wherein R₁₁ is selected from H, C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl.

Embodiment 10 is a composition for use according to embodiment 9,wherein R₁₁ is —CH₃.

Embodiment 11 is a composition for use according to embodiment 9,wherein R₂ is —CH(CH₃)CH₂—O—CHs.

Embodiment 12 is a composition for use according to any of embodiments 1to 7, wherein R₁ is H and R₂ is selected from the group consisting of H,C₁₋₆-alkyl and C₃₋₇-cycloalkyl.

Embodiment 13 is a composition for use according to any of the precedingembodiments, wherein R₁ is H and R₂ is selected from the groupconsisting of H, —CH₃, —CH(CH₃)₂ and cyclopropyl.

Embodiment 14 is a composition for use according to any of the precedingembodiments, wherein R₁ is H and R₂ is —CH(CH₃)₂.

Embodiment 15 is composition for use according to any one of thepreceding embodiments, wherein R₁ is different from R₂.

Embodiment 16 is a composition for use according to any one of thepreceding embodiments, wherein said compound is an S-enantiomer withrespect to the C-atom to which R₂ is bound.

Embodiment 17 is a composition for use according to any embodiments 1 to16, wherein R₁ is H and R₂ is C₁₋₆-alkyl or C₃₋₇-cycloalkyl and whereinsaid compound is an S-enantiomer with respect to the C-atom to which R₂is bound as shown in Formula (III):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof;        -   wherein Y is selected from the group consisting of O, NH,            N—CH₃, CH₂, CH₂—O, S and SO₂;        -   X₁, X₂ and X₃ are selected from the group consisting of, CH            and N;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo.

Embodiment 18 is a composition for use according to any one of thepreceding embodiments wherein R₄ is selected from the group consistingof H, halo, cyano, —CHO, C₁₋₄-alk(en)yl, halo-C₁₋₄-alk(en)yl,—O—C₁₋₄-alk(en)yl.

Embodiment 19 is a composition for use according to any one of thepreceding embodiments wherein m is 0, 1 or 2.

Embodiment 20 is a composition for use according to any one of thepreceding embodiments wherein m is 1.

Embodiment 21 is a composition for use according to any embodiments,wherein X₁ is N, X₂ is N or X₃ is N.

Embodiment 22 is a composition for use according to any one ofembodiments 5 to 20, wherein X₁, X₂ and X₃ is C.

Embodiment 23 is a composition for use according to any one ofembodiments 1 to 4, wherein the compound of Formula (I) is furtherdefined by Formula (IV):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;

-   -   wherein A is an aromatic or heteroaromatic ring selected from        the group consisting of phenyl, naphthyl, biphenyl, quinolinyl,        isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl, triazolyl,        oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and pyridazinyl;    -   R₂ is selected from the group consisting of OR₃, SR₅, S(O)R₅,        S(O)₂R₅, NR₃, NR₃C(O)R₉ or R₃, wherein R₃ is selected from the        group consisting of H, C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉        R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo; or R₁ and R₂ are linked to form a ring;    -   R₄ is selected from the group consisting of H,        C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,        —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo.    -   R₅ is selected from the group consisting of C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo;    -   R₉, R₁₀, R₁₁ are independently selected from H or        C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;    -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl    -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and        C₃₋₆-cycloalk(an/en)diyl.

Embodiment 24 is a composition for use according to embodiment 23,wherein the compound of Formula (IV) is further defined by Formula (V):

wherein

-   -   R₂ is selected from the group consisting of OR₃, SR₅, S(O)R₅,        S(O)₂R₅, NR₃, NR₃C(O)R₉ or R₃, wherein R₃ is selected from the        group consisting of H, C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉        R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo; or R₁ and R₂ are linked to form a ring;    -   R₄ is selected from the group consisting of H,        C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,        —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;    -   R₅ is selected from the group consisting of C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo;    -   R₉, R₁₀, R₁₁ are independently selected from H or        C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;    -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl    -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and        C₃₋₆-cycloalk(an/en)diyl.

Embodiment 25 is a composition for use according to embodiments 23,wherein R₂ is C₁₋₆-alkyl or C₃₋₇-cycloalkyl.

Embodiment 26 is a composition for use according embodiment 25, whereinthe compound of

Formula (V) is further defined by Formula (VI):

-   -   wherein R₄ is selected from the group consisting of H,        C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,        —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;    -   R₉, R₁₀, R₁₁ are independently selected from H or        C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;    -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl    -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and        C₃₋₆-cycloalk(an/en)diyl.

Embodiment 27 is a composition for use according to any one ofembodiments 24 to 26, wherein R₄ is in ortho- or meta position.

Embodiment 28 is a composition for use according to embodiment 1,wherein the compound of Formula (I) is further defined by Formula (VII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof; wherein

-   -   m is 2;    -   Y is selected from the group consisting of O, NH, N—CHs, CH₂,        CH₂—O, S and SO₂;    -   X₁ and X₂ are independently selected from the group consisting        of CH and N;    -   R₂ is selected from the group consisting of —OR₃, —SR₅, —S(O)R₅,        —S(O)₂R₅, —NR₃, —NR₃C(O)R₉ or —R₃, wherein R₃ is selected from        the group consisting of H, C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉        R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo; or R₁ and R₂ are linked to form a ring;    -   R₄ is selected from the group consisting of H,        C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,        —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo; R₂ is selected        from the group consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃,        NR₃C(O)R₉ or R₃, wherein R₃ is selected from the group        consisting of H, C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl,        wherein said C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be        substituted with up to three substituents selected from the        group consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,        —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano,        —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁ and R₂ are        linked to form a ring;    -   R₅ is selected from the group consisting of C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo;    -   R₉, R₁₀, R₁₁ are independently selected from H or        C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;    -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl    -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and        C₃₋₆-cycloalk(an/en)diyl.

Embodiment 29 is a composition for use according to embodiment 28,wherein the compound of Formula (VII) is further defined by Formula(VIII)

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein

-   -   m is 2;    -   Y is selected from the group consisting of O, NH, N—CHs, CH₂,        CH₂—O, S and SO₂;    -   X₂ is selected from the group consisting of, CH and N;    -   R₂ is selected from the group consisting of —OR₃, —SR₅, —S(O)R₅,        —S(O)₂R₅, —NR₃, —NR₃C(O)R₉ or —R₃, wherein R₃ is selected from        the group consisting of H, C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉        R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo; or R₁ and R₂ are linked to form a ring;    -   R₄ is selected from the group consisting of H,        C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,        —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo; R₂ is selected        from the group consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃,        NR₃C(O)R₉ or R₃, wherein R₃ is selected from the group        consisting of H, C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl,        wherein said C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be        substituted with up to three substituents selected from the        group consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,        —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano,        —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁ and R₂ are        linked to form a ring;    -   R₅ is selected from the group consisting of C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo;    -   R₉, R₁₀, R₁₁ are independently selected from H or        C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;    -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl    -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and        C₃₋₆-cycloalk(an/en)diyl.

Embodiment 30 is a composition for use according to any one ofembodiment 5 to 29, wherein Y is O.

Embodiment 31 is a composition for use according to any one ofembodiments 28 to 30, wherein R₂ is selected from the group consistingof H and C₁₋₄-alkyl.

Embodiment 32 is a composition for use according to any one ofembodiments 28 to 31, wherein R₄ is selected from the group consistingof H, —CH₃ and halogen.

Embodiment 33 is a composition for use according to embodiment 32,wherein said compound is further defined by Formula (IX):

Embodiment 34 is a composition for use according to embodiment 28,wherein the compound of Formula (VII) is further defined by Formula (X):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)CH₂—O—CHs, —CH₂—CH₂—CH₃, —CH₂—NH₂,—CH₂—CHF₂, —CH₂—CF₃, —CH₂—NH—CO—CH₃ and —CH₂—NH—SO₂—CH₃ and cyclopropyl,and R₄ is selected from the group consisting of H, Br, Cl, F and I.

Embodiment 35 is a composition for use according to embodiment 28,wherein the compound of Formula (VII) is further defined by any one ofFormulas (XI) to (XXVIII):

Embodiment 36 is a composition for use according to embodiment 28,wherein the compound of Formula (VII) is further defined by Formula(XXIX):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I.

Embodiment 37 is a composition for use according to embodiment 36,wherein the compound of Formula (XXIX) is further defined by Formula(XXX):

Embodiment 38 is a composition for use according to embodiment 28,wherein the compound of Formula (VII) is further defined by Formula(XXXI):

Embodiment 39 is a composition for use according to embodiment 28,wherein the compound of Formula (VII) is further defined by Formula(XXXII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I.

Embodiment 40 is a composition for use according to embodiment 39,wherein the compound of Formula (XXXII) is further defined by Formula(XXXIII):

Embodiment 41 is a composition for use according to embodiment 1,wherein the compound of Formula (I) is further defined by Formula(XXXIV):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂; X₁ is N or C; and R₄ andR′₄ are independently selected from the group consisting of H, Br, Cl, Fand I.

Embodiment 42 is a composition for use according to embodiment 41,wherein Formula (XXXIV) is further defined by Formula (XXXV):

Embodiment 43 is a composition for use according to embodiment 1,wherein the compound of Formula (I) is further defined by any one ofFormulas (XXXVI) to (LIX)

Embodiment 44 is a composition for use according to any one of thepreceding embodiments wherein said prodrug is defined by Formula (LX):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof;    -   wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo; R₂            is selected from the group consisting of OR₃, SR₅, S(O)R₅,            S(O)₂R₅, NR₃, NR₃C(O)R₉ or R₃, wherein R₃ is selected from            the group consisting of H, C₁₋₈-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl may be substituted with up to three            substituents selected from the group consisting of            —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀,            —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁,            fluorinated C₁₋₃-alkyl, nitro and halo; or R₁ and R₂ are            linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo.        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl.        -   R₁₄ is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, pyrimidyl, pyridinyl, thiazolyl,            oxadiazolyl and quinolyl, all aromatic and heteroaromatic            groups optionally substituted by one or more R₄.

Embodiment 45 is a prodrug according to embodiment 44, wherein R₁₄ is aphenyl substituted with methoxy, nitro, cyano, Cl, Br, I and/or F.

Embodiment 46 is a prodrug according to embodiment 44, wherein Formula(LX) is further defined by Formula (LXI):

Embodiment 47 is a composition for use according to any one ofembodiments 1 to 43, wherein said prodrug is defined by Formula (LXII):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof, wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₀ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo.

Embodiment 48 is a composition for use according to any one ofembodiments 1 to 43, wherein said prodrug is defined by Formula (LXIII):

-   -   wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₂,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl

Embodiment 49 is a composition for use according to any one ofembodiments 1 to 43, wherein said prodrug is defined by Formula (LXIV):

wherein

-   -   A is an aromatic or heteroaromatic ring selected from the group        consisting of phenyl, naphthyl, biphenyl, quinolinyl,        isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl, triazolyl,        oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and pyridazinyl;    -   m is 0, 1, 2, 3, 4 or 5;    -   Z is a 2-5 atom chain comprising at least one carbon atom and        optionally one heteroatom or substituted heteroatom, wherein the        heteroatom or substituted heteroatom is selected from the group        consisting of O, N, NC(O)R₃, S, S(O)R₅ and S(O)₂R₅, wherein each        atom of said 2-5 atom chain is optionally substituted with R₁        and R₂;    -   R₁ and R₂ are independently selected from the group consisting        of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or R₃, wherein R₃        is selected from the group consisting of H, C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉        R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo; or R₁ and R₂ are linked to form a ring;    -   R₄ is selected from the group consisting of H,        C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,        —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;    -   B is a 5- to 7-membered heterocyclic.

Embodiment 50 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is myasthenia gravis.

Embodiment 51 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is autoimmune myastheniagravis.

Embodiment 52 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is congenital myastheniagravis.

Embodiment 53 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is Lambert-EatonSyndrome.

Embodiment 54 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is critical illnessmyopathy.

Embodiment 55 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is amyotrophic lateralsclerosis (ALS).

Embodiment 56 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is spinal muscularatrophy (SMA).

Embodiment 57 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is critical illnessmyopathy (CIM).

Embodiment 58 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is reversal diabeticpolyneuropathy.

Embodiment 59 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder is selected from thegroup consisting of Guillain-Barré syndrome, poliomyelitis, post-poliosyndrome, chronic fatigue syndrome, and critical illness polyneuropathy.

Embodiment 60 is a composition for use according to any one of theembodiments, wherein the composition is for use in the treatment ofsymptoms of an indication selected from the group consisting ofmyasthenia gravis (such as autoimmune and congenital myasthenia gravis),Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateralsclerosis (ALS), spinal muscular atrophy (SMA), critical illnessmyopathy (CIM), reversal diabetic polyneuropathy, Guillain-Barrésyndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome,and critical illness polyneuropathy, periodic paralysis, hypokalemicperiodic paralysis and hyperkalemic periodic paralysis.

Embodiment 61 is a composition for use according to any one of theembodiments wherein the neuromuscular disorder has been induced by aneuromuscular blocking agent.

Embodiment 62 is a composition for use according to any one of theembodiments further comprising a pharmaceutically acceptable carrier.

Embodiment 63 is a composition for use according to any one of theembodiments further comprising at least one further active agent.

Embodiment 64 is a composition for use according to any one of theembodiments wherein said further active agent is suitable for treating,preventing or ameliorating said neuromuscular disorder.

Embodiment 65 is a composition for use according to any one of theembodiments, wherein said further active agent is an acetylcholineesterase inhibitor.

Embodiment 66 is a composition for use according to embodiment 65,wherein said acetylcholine esterase inhibitor is selected from the groupconsisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine,neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine,phenanthrene derivatives, galantamine, caffeine-noncompetitive,piperidines, donepezil, tacrine, edrophonium, huperzine, ladostigil,ungeremine and lactucopicrin.

Embodiment 67 is a composition for use according embodiment 65, whereinsaid acetylcholine esterase inhibitor is neostigmine or pyridostigmine.

Embodiment 68 is a composition for use according to any one of theembodiments, wherein said further active agent is suggamadex.

Embodiment 69 is a composition for use according to any one of theembodiments, wherein said further active agent is tirasemtiv.

Embodiment 70 is a composition for use according to any one of theembodiments, wherein said further active agent is 3,4-aminopyridine.

Embodiment 71 is a composition for use according to any one of theembodiments, wherein the composition is administered or adapted foradministration enterally, topically, parenterally or as part of asustained release implant.

Embodiment 72 is a composition for use according to any one of theembodiments, wherein the parenteral administration is intravenous,subcutaneous, intramuscular, intracranial or intraperitoneal.

Embodiment 73 is a composition for use according to any one of theembodiments, wherein the enteral administration is oral, rectal, orbuccal.

Embodiment 74 is a composition for use according to any one of theembodiments, wherein the topical administration is dermal, epicutaneous,vaginal, intravesical, pulmonary, intranasal, intratracheal or as eyedrops.

Embodiment 75 is a composition for use according to any one of theembodiments, wherein the composition is administered or adapted foradministration subcutaneously or intravenously.

Embodiment 76 is a composition for use according to any one of theembodiments, wherein the composition is formulated for oraladministration.

Embodiment 77 is a composition for use according to any one of theembodiments, wherein the composition is formulated in a tablet orcapsule.

Embodiment 78 is a composition for use according to any one of theembodiments, wherein said composition is to be administered in a dosageof from 1 μg/kg-10,000 μg/kg body weight, such as 1 μg/kg-7,500 μg/kg,such as 1 μg/kg-5,000 μg/kg, such as 1 μg/kg-2,000 μg/kg, such as 1μg/kg-1,000 μg/kg, such as 1 μg/kg-700 μg/kg, such as 5 μg/kg-500 μg/kg,such as 10 μg/kg to 100 μg/kg bodyweight.

Embodiment 79 is a composition for use according to any one of theembodiments, wherein said administration is repeated daily.

Embodiment 80 is a composition for use according to any one of theembodiments, wherein said administration is repeated at least 1-3 timesweekly, such as 2-5 times weekly, such as 3-6 times weekly.

Embodiment 81 is a composition for use according to any one of theembodiments, wherein said administration is repeated 1 to 8 times daily,such as 2 to 5 times daily.

Embodiment 82 is a composition for use according to any one of theembodiments, wherein said compound further has been modified in order toincrease its half-life when administered to a patient, in particular itsplasma half-life.

Embodiment 83 is a composition for use according to any one of theembodiments, wherein said compound further comprises a moiety conjugatedto said compound, thus generating a moiety-conjugated compound.

Embodiment 84 is a composition for use according to any one of theembodiments, wherein the moiety-conjugated compound has a plasma and/orserum half-life being longer than the plasma and/or serum half-life ofthe non-moiety conjugated compound.

Embodiment 85 is a composition for use according to any one of theembodiments, wherein the moiety conjugated to the compound is one ormore type(s) of moieties selected from the group consisting of albumin,fatty acids, polyethylene glycol (PEG), acylation groups, antibodies andantibody fragments.

Embodiment 86 is a method of treating, preventing and/or ameliorating aneuromuscular disorder, said method comprising administering atherapeutically effective amount of the composition as defined in anyone of the embodiment to a person in need thereof.

Embodiment 87 is a method of using a composition as defined in any oneof embodiments 1 to 85, for the manufacture of a medicament for thetreatment, prevention and/or amelioration of a neuromuscular disorder.

Embodiment 88 is a composition comprising a compound of Formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂; wherein        -   R₁ and R₂ are independently selected from the group            consisting of —OR₃, —SR₅, —S(O)R₅, —S(O)₂R₅, —NR₃,            —NR₃C(O)R₉ or —R₃, wherein R₃ is selected from the group            consisting of —H, C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl,            wherein said C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may            be substituted with up to three substituents selected from            the group consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂,            —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂,            —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated O₁₋₃-alkyl, nitro and            halo; or R₁ and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of —H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, —O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from —H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl    -   for use in reversing and/or ameliorating a neuromuscular        blockade after surgery.

Embodiment 89 is a method of reversing and/or ameliorating aneuromuscular blockade after surgery, said method comprisingadministering a therapeutically effective amount of the composition asdefined in embodiment 88 to a person in need thereof.

Embodiment 90 is a method for recovery of neuromuscular transmission,said method comprising administering a therapeutically effective amountof the composition as defined in embodiment 88 to a person in needthereof.

Embodiment 91 is a method of using a composition as defined inembodiment 88, for the manufacture of a medicament for recovery ofneuromuscular transmission.

Embodiment 92 is a compound of Formula (I):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   A is an aromatic or heteroaromatic ring selected from the            group consisting of phenyl, naphthyl, biphenyl, quinolinyl,            isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl,            triazolyl, oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and            pyridazinyl;        -   m is 0, 1, 2, 3, 4 or 5;        -   Z is a 2-5 atom chain comprising at least one carbon atom            and optionally one heteroatom or substituted heteroatom,            wherein the heteroatom or substituted heteroatom is selected            from the group consisting of O, N, NC(O)R₃, S, S(O)R₅ and            S(O)₂R₅, wherein each atom of said 2-5 atom chain is            optionally substituted with R₁ and R₂; wherein        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a ring;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, —O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R₅ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl;        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl.

Embodiment 93 is a compound according to embodiment 92, wherein A is amonocyclic or bicyclic aromatic or heteroaromatic ring.

Embodiment 94 is a compound according to any of embodiments 92 and 93,wherein A is five-membered or six-membered aromatic ring.

Embodiment 95 is a compound according to any one of embodiments 92 to93, wherein A is phenyl, or naphthyl.

Embodiment 96 is a compound according to any of embodiments 92 to 95,wherein said compound is a compound of Formula (II):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   m is 0, 1, 2, 3, 4 or 5;        -   Y is selected from the group consisting of O, NH, N—CHs,            CH₂, CH₂—O, S and SO₂;        -   X₁, X₂ and X₃ are independently selected from the group            consisting of CH and N;        -   R₁ and R₂ are independently selected from the group            consisting of OR₃, SR₅, S(O)R₅, S(O)₂R₅, NR₃, NR₃C(O)R₉ or            R₃, wherein R₃ is selected from the group consisting of H,            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo; or R₁            and R₂ are linked to form a C₃₋₆-cycloalk(en)yl or a            halo-C₃₋₆-cycloalk(en)yl;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo;        -   R⁵ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃, nitro and halo; or R₁ and            R₂ are linked to form a ring;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl;        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl.

Embodiment 97 is a compound according to any one of embodiments 92 to96, wherein R₁ is selected from the group consisting of —H and —CH₃.

Embodiment 98 is a compound according to any one of embodiments 92 to96, wherein R₁ is H.

Embodiment 99 is a compound according to any of embodiments 92 to 98,wherein R₁ is H and R₂ is selected from the group consisting of H,C₁₋₄-alk(en)yl, C₃₋₆-cycloalk(en)yl, wherein said C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl may be substituted with up to two substituentsselected from the group consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂—SO₂—R₁₂,—CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉ R₁₀, —S(O)R₁₂, S(O)₂R₁₂,cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl, nitro and halo, wherein R₉, R₁₀,and R₁₁ are independently selected from H, C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl, whereas R₁₂ is selected from C₁₋₄-alk(en/yn)yl andC₃₋₆-cycloalk(en)yl.

Embodiment 100 is a compound according to any of embodiments 92 to 98,wherein R₁ is H and R₂ is selected from the group consisting of H,C₁₋₄-alkyl, C₃₋₆-cycloalkyl and amino-C₁₄-alkyl, wherein said C₁₋₄-alkyland C₃₋₆-cycloalkyl may be substituted with O—R₁₁, wherein R₁₁ isselected from H or C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl.

Embodiment 101 is a compound according to embodiment 100, wherein R₁₁ is—CH₃.

Embodiment 102 is a compound according to embodiment 100, wherein R₂ is—CH(CH₃)CH₂—O—CH₃.

Embodiment 103 is a compound according to any of embodiments 92 to 102,wherein R₁ is H and R₂ is selected from the group consisting of H,C₁₋₆-alkyl and C₃₋₇-cycloalkyl.

Embodiment 104 is a compound according to any of embodiments 92 to 102,wherein R₁ is H and R₂ is selected from the group consisting of H, —CH₃,—CH(CH₃)₂ and cyclopropyl.

Embodiment 105 is a compound according to any one of embodiments 92 to104, wherein R₁ is H and R₂ is —CH(CH₃)₂.

Embodiment 106 is a compound according to any one of embodiments 92 to105, wherein Ru is different from R₂.

Embodiment 107 is a compound according to any one of embodiments 92 to106, wherein said compound is an S-enantiomer with respect to the C-atomto which R₂ is bound.

Embodiment 108 is a compound according to any embodiments 92 to 107,wherein R₁ is H and R₂ is C₁₋₆-alkyl or C₃₋₇-cycloalkyl and wherein saidcompound is an S-enantiomer with respect to the C-atom to which R₂ isbound as shown in Formula (III):

-   -   or a pharmaceutically acceptable salt, solvate, polymorph, or        tautomer thereof; wherein        -   m is 0, 1, 2, 3, 4 or 5        -   Y is selected from the group consisting of O, NH, N—CHs,            CH₂, CH₂—O, S and SO₂;        -   X₁, X₂ and X₃ are independently selected from the group            consisting of CH and N;        -   R₄ is selected from the group consisting of H,            C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,            —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁,            —NR₉R₁₀, cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo,            wherein R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl; R₁₂ is selected            from C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl and R₁₃ is            selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl;        -   R⁵ is selected from the group consisting of            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl, wherein said            C₁₋₈-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl may be substituted            with up to three substituents selected from the group            consisting of —NR₉—CO—R₁₀, —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀,            —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀, —S(O)R₁₂, —S(O)₂R₁₂,            cyano, —O—R₁₁, fluorinated C₁₋₃, nitro and halo; or R₁ and            R₂ are linked to form a ring;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl;        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl.

Embodiment 109 is a compound according to any one of embodiments 92 to108, wherein R₄ is selected from the group consisting of H, halo, cyano,—CHO, C₁₋₄-alk(en)yl, halo-C₁₋₄-alk(en)yl, —O—C₁₋₄-alk(en)yl.

Embodiment 110 is a compound according to any one of embodiments 92 to109, wherein m is 0, 1 or 2.

Embodiment 111 is a compound according to any one of embodiments 92 to110, wherein m is 1.

Embodiment 112 is a compound according to any one of embodiments 92 to111, wherein X₁ is N, X₂ is N or X₃ is N.

Embodiment 113 is a compound according to any one of embodiments 92 to111, wherein X₁, X₂ and X₃ is C.

Embodiment 114 is a compound according to any one of embodiments 92 to113, wherein the compound of Formula (I) is further defined by Formula(IV):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof; wherein

-   -   A is an aromatic or heteroaromatic ring selected from the group        consisting of phenyl, naphthyl, biphenyl, quinolinyl,        isoquinolinyl, imidazolyl, thiazolyl, thiadiazolyl, triazolyl,        oxazolyl, pyridinyl, pyrimidinyl, pyrazyl, and pyridazinyl;    -   R₂ is selected from the group consisting of OR₃, SR₅, S(O)R₅,        S(O)₂R₅, NR₃, NR₃C(O)R₉ or R₃, wherein R₃ is selected from the        group consisting of H, C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂—SO₂—R₁₂, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉        R₁₀, —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃-alkyl,        nitro and halo; or R₁ and R₂ are linked to form a ring;    -   R₄ is selected from the group consisting of H,        C₁₋₆-alk(en/yn)yl, C₃₋₆-cycloalk(en)yl, —NR₉—CO—R₁₀,        —NR₁₀—SO₂—R₁₁, —CO—NR₉R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        cyano, O—R¹¹, fluorinated C₁₋₃, nitro and halo, wherein R₉, R₁₀,        R₁₁ are independently selected from H or C₁₋₄-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl; R₁₂ is selected from C₁₋₄-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl and R₁₃ is selected from        C₁₋₄-alk(an/en/yn)diyl and C₃₋₆-cycloalk(an/en)diyl;    -   R⁵ is selected from the group consisting of C₁₋₈-alk(en/yn)yl        and C₃₋₆-cycloalk(en)yl, wherein said C₁₋₈-alk(en/yn)yl and        C₃₋₆-cycloalk(en)yl may be substituted with up to three        substituents selected from the group consisting of —NR₉—CO—R₁₀,        —N(R₁₀)₂SO₂—R₁₂, —CO—NR₉ R₁₀, —SO₂—NR₉ R₁₀, —R₁₃—O—R₁₁, —NR₉R₁₀,        —S(O)R₁₂, —S(O)₂R₁₂, cyano, —O—R₁₁, fluorinated C₁₋₃, nitro and        halo; or R₁ and R₂ are linked to form a ring;        -   R₉, R₁₀, R₁₁ are independently selected from H or            C₁₋₄-alk(en/yn)yl and C₃₋₆-cycloalk(en)yl;        -   R₁₂ is selected from C₁₋₄-alk(en/yn)yl and            C₃₋₆-cycloalk(en)yl;        -   R₁₃ is selected from C₁₋₄-alk(an/en/yn)diyl and            C₃₋₆-cycloalk(an/en)diyl.

Embodiment 115 is a compound according to embodiment 114, wherein thecompound of Formula (IV) is further defined by Formula (V):

wherein R₂ and R₄ are as defined above.

Embodiment 116 is a compound according to embodiment 114 or embodiment115, wherein R₂ is C₁₋₆-alkyl or C₃₋₇-cycloalkyl.

Embodiment 117 is a compound according embodiment 115, wherein thecompound of Formula (V) is further defined by Formula (VI):

wherein R₄ is as defined above.

Embodiment 118 is a compound according to any one of embodiments 115 to117, wherein R₄ is in ortho- or meta position.

Embodiment 119 is a compound according to embodiment 92, wherein thecompound of Formula (I) is further defined by Formula (VII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein m is 2 and X₁, X₂, Y, R₂ and R₄ are as defined above.

Embodiment 120 is a compound according to embodiment 119, wherein thecompound of Formula (VII) is further defined by Formula (VIII)

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein m, X₂, Y, R₂ and R₄ are as defined above.

Embodiment 121 is a compound according to any one of embodiments 92 to120, wherein Y is 0.

Embodiment 122 is a compound according to any one of embodiments 92 to121, wherein R₂ is selected from the group consisting of H andC₁₋₄-alkyl.

Embodiment 123 is a compound according to any one of embodiments 92 to122, wherein R₄ is selected from the group consisting of H, —CH₃ andhalogen.

Embodiment 124 is a compound according to any one of embodiments 92 to123, wherein said compound is further defined by Formula (IX):

Embodiment 125 is a compound according to embodiment 119, wherein thecompound of Formula (VII) is further defined by Formula (X):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)CH₂—O—CH₃, —CH₂—CH₂—CH₃, —CH₂—NH₂,—CH₂—CHF₂, —CH₂—CF₃, —CH₂—NH—CO—CH₃ and —CH₂—NH—SO₂—CH₃ and cyclopropyl,and R₄ is selected from the group consisting of H, Br, Cl, F and I.

Embodiment 126 is a compound se according to embodiment 119, wherein thecompound of Formula (VII) is further defined by any one of Formulas (XI)to (XXVIII) as defined in embodiment 35.

Embodiment 127 is a compound according to embodiment 119, wherein thecompound of Formula (VII) is further defined by Formula (XXIX):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I.

Embodiment 128 is a compound according to embodiment 127, wherein thecompound of Formula (XXIX) is further defined by Formula (XXX):

Embodiment 129 is a compound according to embodiment 119, wherein thecompound of Formula (VII) is further defined by Formula (XXXI):

Embodiment 130 is a compound according to embodiment 119, wherein thecompound of Formula (VII) is further defined by Formula (XXXII):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂ and R₄ is selected fromthe group consisting of H, Br, Cl, F and I.

Embodiment 131 is a compound according to embodiment 130, wherein thecompound of Formula (XXXII) is further defined by Formula (XXXIII):

Embodiment 132 is a compound according to embodiment 92, wherein thecompound of Formula (I) is further defined by Formula (XXXIV):

or a pharmaceutically acceptable salt, solvate, polymorph, or tautomerthereof;wherein R₂ is selected from the group consisting of —CH₃, —CH₂—CH₃,—CH(CH₃)₂, —C(CH₃)₃, —CH₂—CH₂—CH₃ and —CH₂—NH₂; X₁ is N or C; and R₄ andR′₄ are independently selected from the group consisting of H, Br, Cl, Fand I.

Embodiment 133 is a compound according to embodiment 132, whereinFormula (XXXIV) is further defined by Formula (XXXV):

Embodiment 134 is a compound according to embodiment 92, wherein thecompound of Formula (I) is further defined by any one of Formulas(XXXVI) to (LIX) as defined in embodiment 43.

Embodiment 135 is a compound of Formula (I.2):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;        -   with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

Embodiment 136 is a compound according to embodiment 135, wherein thecompound is of Formula (II.2):

-   -   wherein:        -   R¹ is selected from the group consisting of F, Cl, Br, I,            —CN, —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₄            cycloalkyl and —S—CH₃;        -   R² is independently selected from the group consisting of            hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime            optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more, identical or            different, substituents R⁵;        -   R⁴ is selected from the group consisting of H and C₁₋₅            alkyl;        -   R⁵ is independently selected from the group consisting of F            and OH; and        -   n is an integer 0, 1 or 2;        -   or a pharmaceutically acceptable salt, hydrate, polymorph,            tautomer, or solvate thereof;        -   with the proviso that when R¹ is Cl, R⁴ is H and n is 0,            then R³ is not methyl or ethyl.

Embodiment 137 is a compound according to any one of the precedingembodiments, wherein R⁴ is H.

Embodiment 138 is a compound according to any one of the precedingembodiments, wherein R⁴ is the sodium counterion.

Embodiment 139 is a compound according to any one of the precedingembodiments, wherein n is 0.

Embodiment 140 is a compound according to any one of the precedingembodiments, wherein

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₁₋₄ alkenyl, C₁₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R³ is is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅        alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which may        be optionally substituted with one or more F; and    -   R⁴ is selected from the group consisting of H and C₁₋₅ alkyl,        preferably H;    -   n is 0;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 141 is a compound according to embodiment 140, wherein R³ isselected from the group consisting of methyl, ethyl, n-propyl orisopropyl optionally substituted with one or more, identical ordifferent, substituents R⁵.

Embodiment 142 is a compound according to any one of the precedingembodiments, wherein R³ is methyl.

Embodiment 143 is a compound according to any one of the precedingembodiments, wherein R³ is ethyl

Embodiment 144 is a compound according to any one of the precedingembodiments, wherein R³ is n-propyl or isopropyl.

Embodiment 145 is a compound according to any one of the precedingembodiments, wherein R³ is C₁₋₅ alkyl substituted with one or more F.

Embodiment 146 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂ and —CH₂CF₃, preferably —CH₂F.

Embodiment 147 is a compound according to any one of the precedingembodiments, wherein R³ is C₂₋₅ alkenyl, optionally substituted with oneor more, identical or different, substituents R⁵.

Embodiment 148 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofethenyl, propenyl, isopropenyl, butenyl, isobutenyl and pentenyl,optionally substituted with one or more F.

Embodiment 149 is a compound according to any one of the precedingembodiments, wherein R³ is C₃₋₅ cycloalkyl, optionally substituted withone or more F.

Embodiment 150 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl and cyclobutylmethyl, optionally substituted with oneor more F.

Embodiment 151 is a compound according to any one of the precedingembodiments, wherein R³ is cycloalkenyl, optionally substituted with oneor more F.

Embodiment 152 is a compound according to any one of the precedingembodiments, wherein R² is deuterium.

Embodiment 153 is a compound according to any one of the precedingembodiments, wherein the compound is of Formula (III.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, I, and -oxime optionally substituted with C₁ alkyl;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H.    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 154 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of methyl,ethyl, n-propyl or isopropyl optionally substituted with one or more,identical or different, substituents R⁵.

Embodiment 155 is a compound according to any one of the precedingembodiments, wherein R³ is methyl.

Embodiment 156 is a compound according to any one of the precedingembodiments, wherein R³ is ethyl

Embodiment 157 is a compound according to any one of the precedingembodiments, wherein R³ is n-propyl or isopropyl.

Embodiment 158 is a compound according to any one of the precedingembodiments, wherein R³ is C₁₋₅ alkyl substituted with one or more F.

Embodiment 159 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂ and —CH₂CF₃, preferably —CH₂F.

Embodiment 160 is a compound according to any one of the precedingembodiments, wherein R³ is C₂₋₅ alkenyl, optionally substituted with oneor more, identical or different, substituents R⁵.

Embodiment 161 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofethenyl, propenyl, isopropenyl, butenyl, isobutenyl and pentenyl,optionally substituted with one or more F.

Embodiment 162 is a compound according to any one of the precedingembodiments, wherein R³ is C₃₋₅ cycloalkyl, optionally substituted withone or more F.

Embodiment 163 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl and cyclobutylmethyl, optionally substituted with oneor more F.

Embodiment 164 is a compound according to any one of the precedingembodiments, wherein R³ is cycloalkenyl, optionally substituted with oneor more F.

Embodiment 165 is a compound according to any one of any one of thepreceding embodiments, wherein R¹ is different from R².

Embodiment 166 is a compound according to any one of the precedingembodiments, wherein the compound is of Formula (IV.2):

-   -   wherein:        -   R¹ is selected from the group consisting of Cl, Br, and I;        -   R² is selected from the group consisting of deuterium, F,            Cl, Br, and I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H.    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 167 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of methyl,ethyl, n-propyl or isopropyl optionally substituted with one or more,identical or different, substituents R⁵.

Embodiment 168 is a compound according to any one of the precedingembodiments, wherein R³ is methyl.

Embodiment 169 is a compound according to any one of the precedingembodiments, wherein R³ is ethyl

Embodiment 170 is a compound according to any one of the precedingembodiments, wherein R³ is n-propyl or isopropyl.

Embodiment 171 is a compound according to any one of the precedingembodiments, wherein R³ is C₁₋₅ alkyl substituted with one or more F.

Embodiment 172 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂ and —CH₂CF₃, preferably —CH₂F.

Embodiment 173 is a compound according to any one of the precedingembodiments, wherein R³ is C₂₋₅ alkenyl, optionally substituted with oneor more, identical or different, substituents R⁵.

Embodiment 174 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofethenyl, propenyl, isopropenyl, butenyl, isobutenyl and pentenyl,optionally substituted with one or more F.

Embodiment 175 is a compound according to any one of the precedingembodiments, wherein R³ is C₃₋₅ cycloalkyl, optionally substituted withone or more F.

Embodiment 176 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl and cyclobutylmethyl, optionally substituted with oneor more F.

Embodiment 177 is a compound according to any one of the precedingembodiments, wherein R³ is cycloalkenyl, optionally substituted with oneor more F.

Embodiment 178 is a compound according to any one of the precedingembodiments, wherein R¹ is different from R².

Embodiment 179 is a compound according to any one of the precedingembodiments, wherein n is 2.

Embodiment 180 is a compound according to any one of the precedingembodiments, wherein the compound is of Formula (V) or (VI):

-   -   wherein:        -   R¹ is Br, Cl or I;        -   R² is independently deuterium, F, Cl, Br, or I;        -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₁₋₅            alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which            may be optionally substituted with one or more F; and        -   R⁴ is selected from the group consisting of H or C₁₋₅ alkyl;            preferably H;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 181 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of methyl,ethyl, n-propyl or isopropyl optionally substituted with one or more,identical or different, substituents R⁵.

Embodiment 182 is a compound according to any one of the precedingembodiments, wherein R³ is methyl.

Embodiment 183 is a compound according to any one of the precedingembodiments, wherein R³ is ethyl

Embodiment 184 is a compound according to any one of the precedingembodiments, wherein R³ is n-propyl or isopropyl.

Embodiment 185 is a compound according to any one of the precedingembodiments, wherein R³ is C₁₋₅ alkyl substituted with one or more F.

Embodiment 186 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of —CH₂F,—CHF₂, —CF₃, —CH₂CH₂F, —CH₂CHF₂ and —CH₂CF₃, preferably —CH₂F.

Embodiment 187 is a compound according to any one of the precedingembodiments, wherein R³ is C₂₋₅ alkenyl, optionally substituted with oneor more, identical or different, substituents R⁵.

Embodiment 188 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofethenyl, propenyl, isopropenyl, butenyl, isobutenyl and pentenyl,optionally substituted with one or more F.

Embodiment 189 is a compound according to any one of the precedingembodiments, wherein R³ is C₃₋₅ cycloalkyl, optionally substituted withone or more F.

Embodiment 190 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting ofcyclopropyl, cyclobutyl, cyclopentyl, cyclopropylmethyl,cyclopropylethyl and cyclobutylmethyl, optionally substituted with oneor more F.

Embodiment 191 is a compound according to any one of the precedingembodiments, wherein R³ is cycloalkenyl, optionally substituted with oneor more F.

Embodiment 192 is a compound according to any one of the precedingembodiments, wherein R¹ is different from R².

Embodiment 193 is a compound according to any one of the precedingembodiments, wherein R¹ is Br.

Embodiment 194 is a compound according to any one of the precedingembodiments, wherein R² is deuterium or F.

Embodiment 195 is a compound according to any one of the precedingembodiments, wherein the oxime is an aldoxime.

Embodiment 196 is a compound according to any one of the precedingembodiments, wherein the -oxime optionally substituted with C₁ alkyl is

Embodiment 197 is a compound according to any one of the precedingembodiments, wherein, the compound is selected from the group consistingof:

Embodiment 198 is a compound according to any one of the proceedingembodiments, wherein the compound is selected from the group consistingof:

-   (2R)-2-[4-bromo(3,5-²H₂)phenoxy]-3-fluoropropanoic acid;-   (2S)-2-[4-bromo(3,5-²H₂)phenoxy]propanoic acid;-   ethyl (2S)-2-(4-bromo-2-fluorophenoxy)-3-methylbut-3-enoate;-   (2R)-2-[4-bromo(2,6-²H₂)phenoxy]-3-fluoropropanoic acid;-   (2S)-2-[4-bromo(2,6-²H₂)phenoxy]propanoic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)propanoic acid;-   (2R)-2-(4-bromo-2-fluorophenoxy)-3,3-difluoropropanoic acid;-   (2S)-2-{4-bromo-2-[(1E)-(methoxyimino)methyl]phenoxy}propanoic acid;-   (2S)-2-(2-bromo-4-chlorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(2-fluoro-4-iodophenoxy)propanoic acid;-   (2S)-2-(2-bromo-4-iodophenoxy)propanoic acid;-   ethyl 2-(4-bromo-2-fluorophenoxy)-3,3,3-trifluoropropanoate;-   ethyl 2-(4-bromophenoxy)-3,3,3-trifluoropropanoate;-   (2S)-2-(2-chloro-4-iodophenoxy)propanoic acid;-   (2S)-2-(2-bromo-4-chlorophenoxy)propanoic acid;-   2-(4-bromophenoxy)-2-cyclopentylacetic acid;-   (2R)-2-(4-bromo-2-fluorophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-chloro-2-fluorophenoxy)-3-methylbutanoic acid;-   (2R)-2-(2-bromo-4-chlorophenoxy)-3-fluoropropanoic acid;-   (2R)-2-(4-chlorophenoxy)-3-fluoropropanoic acid;-   (2R)-2-(4-chloro-2-fluorophenoxy)-3-fluoropropanoic acid;-   (2R)-2-(2,4-dibromophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-bromophenoxy)-3-hydroxypropanoic acid;-   (2R)-2-(4-bromophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(3-bromo-4-chlorophenoxy)propanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)propanoic acid;-   (2S)-2-[4-(trifluoromethyl)phenoxy]propanoic acid;-   sodium (2S)-2-(4-chlorophenoxy)-5-methylhexanoate;-   methyl (2S)-2-(4-chlorophenoxy)-5-methylhexanoate;-   sodium (2S)-2-(4-chlorophenoxy)-4-methylpentanoate;-   sodium (2S)-2-(4-chlorophenoxy)hexanoic acid;-   methyl (2S)-2-(4-chlorophenoxy)hexanoate;-   (2S)-2-(4-chloro-2-fluorophenoxy)propanoic acid;-   (2S)-2-(3,4-dichlorophenoxy)propanoic acid;-   (2S)-2-(2,4-dibromophenoxy)propanoic acid;-   (2S)-2-[4-(prop-1-yn-1-yl)phenoxy]propanoic acid;-   (2S)-2-(4-ethynylphenoxy)propanoic acid;-   sodium (2S)-2-(4-chlorophenoxy)butanoate;-   sodium (2S)-2-(2,4-dichlorophenoxy)propanoate;-   sodium (2S)-2-(4-chlorophenoxy)-3-methylbutanoate;-   sodium (2S)-2-(4-ethylphenoxy)propanoate;-   sodium (2S)-2-(4-cyanophenoxy)propanoate;-   sodium (2S)-2-[4-(methylsulfanyl)phenoxy]propanoate;-   methyl (2S)-2-(4-ethynylphenoxy)propanoate;-   methyl (2S)-2-(4-bromophenoxy)propanoate;-   methyl (2S)-2-(4-chlorophenoxy)butanoate;-   2,2,2-trifluoroethyl (2S)-2-(4-chlorophenoxy)propanoate;-   propan-2-yl (2S)-2-(4-chlorophenoxy)propanoate;-   methyl (2S)-2-(4-chlorophenoxy)propanoate;-   (2S)-2-(4-bromo-2,6-difluorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(4-bromophenoxy)butanoic acid;-   (2S)-2-(4-cyclobutylphenoxy)propanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)butanoic acid-   (2S,3E)-2-(4-bromophenoxy)-4-fluorobut-3-enoic acid;-   (2S)-2-(4-bromophenoxy)(2-²H)butanoic acid;-   (2S)-2-(4-bromophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)pentanoic acid;-   (2S)-2-(2,4-dibromophenoxy)pentanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)pentanoic acid;-   (2S)-2-(4-bromophenoxy)-3-cyclopropylpropanoic acid;-   (2S)-2-(2,4-dibromophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromophenoxy)-2-cyclopropylacetic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)pent-4-ynoic acid;-   (2S)-2-(4-bromophenoxy)pentanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-2-cyclobutylacetic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-3-cyclopropylpropanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(2,4-dibromophenoxy)-3-methoxypropanoic acid;-   (2S)-2-(4-bromophenoxy)but-3-enoic acid;-   (2S)-2-(4-bromophenoxy)(3,4-²H₂)butanoic acid;-   (2R)-2-(4-bromo-2-chlorophenoxy)-3-fluoropropanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)butanoic acid;-   (2S)-2-(4-bromo-3-fluorophenoxy)-3-methylbutanoic acid;-   (2S)-2-(4-bromo-2-chlorophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromo-2,3-difluorophenoxy)-3-methylbutanoic acid;-   (2R)-2-(4-bromophenoxy)-3-fluoro(2-²H)propanoic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromophenoxy)-2-cyclobutylacetic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-2-cyclobutylacetic acid;-   (2S)-2-(4-bromophenoxy)-4-fluorobutanoic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)-3-methylbutanoic acid;-   (2S)-2-(4-bromo-2-fluorophenoxy)-2-cyclopropylacetic acid;-   (2S)-2-(4-bromo-2-iodophenoxy)butanoic acid;-   (2S)-2-(4-chloro-2-fluorophenoxy)butanoic acid;-   (2S)-2-cyclopropyl-2-(2,4-dibromophenoxy)acetic acid,-   (2S)-2-(4-bromo-2-chlorophenoxy)-2-cyclopropylacetic acid,-   (2R,3R)-2-(4-bromophenoxy)-3-fluorobutanoic acid, and-   (2R,3R)-2-(4-bromo-2-fluorophenoxy)-3-fluorobutanoic acid.

Embodiment 199 is a compound according to any one of the embodiments,wherein the compound has activity on CIC-1 receptor.

Embodiment 200 is a compound according to any one of the embodiments,wherein the compound is an inhibitor of the CIC-1 ion channel.

Embodiment 201 is a compound according to any one of the embodiments,wherein the EC₅₀<50 μM, preferably <40 μM, more preferably <30 μM, morepreferably <20 μM, more preferably <15 μM, even more preferably <10 μMand most preferably <5 μM.

Embodiment 202 is a compound according to any one of the embodiments,wherein the recovery of force in muscles with neuromuscular dysfunctionis >5%, preferably >10%, more preferably >15%, more preferably >20%,more preferably >25%, even more preferably >30% and most preferably>35%.

Embodiment 203 is a compound according to any one of the embodiments,wherein the compound improves the recovered force in isolated rat soleusmuscles after exposure to tubocurarine.

Embodiment 204 is a composition comprising the compound of any one ofthe embodiments.

Embodiment 205 is a composition according to any one of the embodiments,wherein the composition is a pharmaceutical composition.

Embodiment 206 is a compound according to any one of the embodiments, orthe composition according to any one of embodiments 204 to 205, for useas a medicament.

Embodiment 207 is a composition according to any one of embodiments 204to 206, wherein the composition further comprises a pharmaceuticallyacceptable carrier.

Embodiment 208 is a composition according to any one of embodiments 204to 207 wherein the composition further comprises at least one furtheractive agent.

Embodiment 209 is a composition according to embodiments 208, whereinsaid further active agent is suitable for treating, preventing orameliorating said neuromuscular disorder.

Embodiment 210 is a composition according to any one of embodiments 208to 209, wherein said further active agent is an acetylcholine esteraseinhibitor.

Embodiment 211 is a composition according to embodiment 210, whereinsaid acetylcholine esterase inhibitor is selected from the groupconsisting of delta-9-tetrahydrocannabinol, carbamates, physostigmine,neostigmine, pyridostigmine, ambenonium, demecarium, rivastigmine,phenanthrene derivatives, galantamine, piperidines, donepezil, tacrine,edrophonium, huperzine, ladostigil, ungeremine and lactucopicrin.

Embodiment 212 is a composition according to embodiment 210, whereinsaid acetylcholine esterase inhibitor is neostigmine or pyridostigmine.

Embodiment 213 is a composition according to any one of embodiments 208to 209, wherein said further active agent is suggamadex.

Embodiment 214 is a composition according to any one of embodiments 208to 209, wherein said further active agent is tirasemtiv or CK-2127107.

Embodiment 215 is a composition according to any one of embodiments 208to 209, wherein said further active agent is 3,4-aminopyridine.

Embodiment 216 is a method for manufacturing the compound according toany one of embodiments 135 to 198, the method comprising the steps of

-   -   a. reacting a compound having a formula of

-   -   wherein R³ is as defined in any one of embodiments 135 to 198        and R⁶ is selected from the group consisting of alkyl, alkenyl,        akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic        ring and -alkylene-Si-alkyl, with first a reagent capable of        converting the alcohol (OH) into a leaving group and secondly        with a compound having a formula of

-   -   wherein R¹, R² and n are as defined in any one of embodiments        135 to 198 and Y is 0 to generate a compound having a formula of

and

-   -   b. reacting the product compound of a) with an ester hydrolysing        reagent thus generating a compound according to any one of        embodiments 135 to 198.

Embodiment 217 is a method for manufacturing the compound according toany one of embodiments 135 to 198, the method comprising the steps of

-   -   b. reacting a compound having a formula of

-   -   wherein R¹, R² and n are as defined in any one of items v and Q        is a leaving group selected from the group consisting of        fluorine and iodine, with a compound having a formula of

-   -   wherein R³ is as defined in any one of embodiments 135 to 198        and R⁶ is selected from the group consisting of alkyl, alkenyl,        akynyl, cycloalkyl, cycloalkenyl, aromatic ring, heteroaromatic        ring and -alkylene-Si-alkyl to generate a compound having a        formula of

-   -   wherein Y is O; and    -   c. reacting the product compound of a) with an ester hydrolysing        reagent thus generating a compound according to any one of        embodiments 135 to 198.

Embodiment 218 is a method for manufacturing the compound according toany one of embodiments 135 to 198, the method comprising the steps of

-   -   c. reacting a compound having a formula of

-   -   wherein R³ is as defined in any one of embodiments 135 to 198, Z        is OH and R⁷ is selected from the group consisting of —Si-alkyl,        with first a reagent capable of converting the alcohol (Z) into        a leaving group and secondly with a compound having a formula of

-   -   wherein R¹, R² and n are as defined in any one of embodiments        135 to 198 and Y is O to generate a compound having a formula of

-   -   c. reacting the product compound of a) with an ether cleaving        reagent to generate a compound having a formula of

and

-   -   d. reacting the product compound of b) with an oxidising agent        thus generating a compound according to any one of embodiments        135 to 198.

Embodiment 219 is a compound according to any one of the embodiments foruse in treating, ameliorating and/or preventing a neuromusculardisorder, and/or for use in reversing and/or ameliorating aneuromuscular blockade.

Embodiment 220 is a compound for use according to any one of theembodiments, wherein the compound improves the recovered force inisolated rat soleus muscles after exposure to tubocurarine.

Embodiment 221 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is myasthenia gravis.

Embodiment 222 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is autoimmune myastheniagravis.

Embodiment 223 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is congenital myastheniagravis.

Embodiment 224 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is Lambert-EatonSyndrome.

Embodiment 225 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is critical illnessmyopathy.

Embodiment 226 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is amyotrophic lateralsclerosis (ALS).

Embodiment 227 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is spinal muscularatrophy (SMA).

Embodiment 228 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is critical illnessmyopathy (CIM).

Embodiment 229 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is Charcot-Marie toothdisease (CMT).

Embodiment 230 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is sarcopenia.

Embodiment 231 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is reversal diabeticpolyneuropathy.

Embodiment 232 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder is selected from thegroup consisting of Guillain-Barré syndrome, poliomyelitis, post-poliosyndrome, chronic fatigue syndrome, and critical illness polyneuropathy.

Embodiment 233 is a compound for use according to any one of theembodiments, wherein the compound is for use in the treatment ofsymptoms of an indication selected from the group consisting ofmyasthenia gravis (such as autoimmune and congenital myasthenia gravis),Lambert-Eaton Syndrome, critical illness myopathy, amyotrophic lateralsclerosis (ALS), spinal muscular atrophy (SMA), critical illnessmyopathy (CIM), reversal diabetic polyneuropathy, Guillain-Barrésyndrome, poliomyelitis, post-polio syndrome, chronic fatigue syndrome,and critical illness polyneuropathy, periodic paralysis, hypokalemicperiodic paralysis and hyperkalemic periodic paralysis.

Embodiment 234 is a compound for use according to any one of theembodiments wherein the neuromuscular disorder has been induced by aneuromuscular blocking agent.

Embodiment 235 is a compound for use according to any one of theembodiments, wherein the neuromuscular blockade is neuromuscularblockade after surgery.

Embodiment 236 is a compound for use according to any one of theembodiments, wherein the neuromuscular blockade is drug induced.

Embodiment 237 is a compound for use according to embodiment 236,wherein the drug is an antibiotic.

Embodiment 238 is a compound for use according to embodiment 236,wherein the drug is a non-depolarizing neuromuscular blocker.

Embodiment 239 is a compound for use according to any one of theembodiments, wherein said compound further has been modified in order toincrease its half-life when administered to a patient, in particular itsplasma half-life.

Embodiment 240 is a compound for use according to any one of theembodiments, wherein said compound further comprises a moiety conjugatedto said compound, thus generating a moiety-conjugated compound.

Embodiment 241 is a compound for use according to any one of theembodiments, wherein the moiety-conjugated compound has a plasma and/orserum half-life being longer than the plasma and/or serum half-life ofthe non-moiety conjugated compound.

Embodiment 242 is a compound for use according to any one of theembodiments, wherein the moiety conjugated to the compound is one ormore type(s) of moieties selected from the group consisting of albumin,fatty acids, polyethylene glycol (PEG), acylation groups, antibodies andantibody fragments.

Embodiment 243 is a compound for use according to any one of theembodiments, wherein said compound is comprised in a composition.

Embodiment 244 is a compound for use according to any one of theembodiments, wherein the composition is a pharmaceutical composition.

Embodiment 245 is a compound for use according to any one of theembodiments, wherein the composition further comprises apharmaceutically acceptable carrier.

Embodiment 246 is a compound for use according to any one of theembodiments, wherein the composition further comprises at least onefurther active agent.

Embodiment 247 is a compound for use according to any one of theembodiments, wherein said further active agent is suitable for treating,preventing or ameliorating said neuromuscular disorder.

Embodiment 248 is a compound for use according to any one of theembodiments, wherein said further active agent is an acetylcholineesterase inhibitor.

Embodiment 249 is a compound for use according to any one of theembodiments, wherein said acetylcholine esterase inhibitor is selectedfrom the group consisting of Delta9-tetrahydrocannabinol, carbamates,physostigmine, neostigmine, pyridostigmine, ambenonium, demecarium,rivastigmine, phenanthrene derivatives, galantamine, piperidines,donepezil, tacrine, edrophonium, huperzine, ladostigil, ungeremine andlactucopicrin.

Embodiment 250 is a compound for use according to any one of theembodiments, wherein said acetylcholine esterase inhibitor isneostigmine or pyridostigmine.

Embodiment 251 is a compound for use according to any one of theembodiments, wherein said further active agent is suggamadex.

Embodiment 252 is a compound for use according to any one of theembodiments, wherein said further active agent is tirasemtiv orCK-2127107.

Embodiment 253 is a compound for use according to any one of theembodiments, wherein said further active agent is 3,4-aminopyridine.

Embodiment 254 is a method of treating, preventing and/or ameliorating aneuromuscular disorder, said method comprising administering atherapeutically effective amount of the compound as defined in any oneof the embodiments to a person in need thereof.

Embodiment 255 is a method of using of a compound as defined in any oneof embodiments 135 to 198, for the manufacture of a medicament for thetreatment, prevention and/or amelioration of a neuromuscular disorder,and/or for reversing and/or ameliorating of a neuromuscular blockade.

Embodiment 256 is a method of reversing and/or ameliorating aneuromuscular blockade, said method comprising administering atherapeutically effective amount of the compound as defined in any oneof the embodiments to a person in need thereof.

Embodiment 257 is a method for recovery of neuromuscular transmission,said method comprising administering a therapeutically effective amountof the compound as defined in any one of the embodiments to a person inneed thereof.

Embodiment 258 is a method for recovering neuromuscular transmission,the method comprising administering a compound as defined in any one ofthe embodiments to an individual in need thereof.

Embodiment 259 is a compound of Formula (Ia):

wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R² is independently selected from the group consisting of        hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime        optionally substituted with C₁ alkyl;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷, OC₃₋₅ cycloalkyl        optionally substituted with one or more, identical or different,        substituents R⁷, and OH;    -   R⁶ is independently selected from the group consisting of        hydrogen and deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and    -   n is an integer 0, 1, 2, 3 or 4;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 260 is a compound according to embodiment 259, when R¹ is Cl,R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1 or 2, then R³ is notmethyl.

Embodiment 261 is a compound according to any of embodiments 259 and260, wherein when R¹ is Cl, R⁴ is H or Me or 4-methoxyphenyl or4-nitrophenyl, R⁵ is H, R⁶ is H and n is 0, then R³ is not methyl; whenR¹ is Br, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is not methyl orisopropyl; when R¹ is Br, R⁴ is Me, R⁵ is H, R⁶ is H and n is 0, then R³is not isopropyl; and when R¹ is I, R⁴ is H, R⁵ is H, R⁶ is H and n is0, then R³ is not methyl.

Embodiment 262 is a compound according to any of embodiments 259-261,wherein when R¹ is Cl, R² is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 1,then R³ is not ethyl.

Embodiment 263 is a compound according to any of embodiments 259-262,wherein when R³ is Me, R⁴ is Et, R⁵ is H, R⁶ is H and n is 0, then R¹ isnot F, Cl, Br, —CN or —CF₃ and when R² is Cl, R³ is Me, R⁴ is Me, Et,cyclohexyl, cyclopentyl or n-Butyl, R⁵ is H, R⁶ is H and n is 1, then R¹is not C₁.

Embodiment 264 is a compound according to any of embodiments 259-263,wherein when R³ is Me, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R¹ isnot F, Cl, Br, I, —CH₃ or —CF₃.

Embodiment 265 is a compound according to any of embodiments 259-264,wherein R¹ is Cl, R⁴ is H, R⁵ is H, R⁶ is H and n is 0, then R³ is notEt, n-propyl or isopropyl and when R¹ is Br, R⁴ is H, R⁵ is H, R⁶ is Hand n is 0, then R³ is not cyclopropyl, 1,1-difluoroethan-2-yl,1-methoxypropan-2-yl or 1-ethoxycyclobutan-3-yl.

Embodiment 266 is a compound according to any of embodiments 259-265,wherein the compound is of Formula (IIa):

wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R² is independently selected from the group consisting of        hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime        optionally substituted with C₁ alkyl;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷, OC₃₋₅ cycloalkyl        optionally substituted with one or more, identical or different,        substituents R⁷, and OH;    -   R⁶ is independently selected from the group consisting of        hydrogen and deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and    -   n is an integer 0, 1, 2, 3 or 4;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 267 is a compound according to any of embodiments 259-266,wherein the compound is of Formula (VII.2):

wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R² is independently selected from the group consisting of        hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime        optionally substituted with C₁ alkyl;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 268 is a compound according to any of embodiments 259-267,wherein the compound is of Formula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of Cl and Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 269 is a compound according to any of embodiments 259-268,wherein the compound is of Formula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl and C₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 270 is a compound according to any of embodiments 259-269,wherein the compound is of Formula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which is substituted with one or more, identical or        different, substituents R⁵; and    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 271 is a compound according to any of embodiments 259-270,wherein the compound is of Formula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₄ cycloalkyl        and —S—CH₃;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br and I;    -   R³ is selected from the group consisting of fluoromethyl,        fluoroethyl and fluoropropyl, each of which may be optionally        substituted with one or more deuterium;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 272 is a compound according to any one of the precedingembodiments, wherein R⁴ is H.

Embodiment 273 is a compound according to any one of the precedingembodiments, wherein R⁴ is the sodium counterion.

Embodiment 274 is a compound according to any of embodiments 259-266,wherein the compound is an embodiment of the compound of Formula(VII.2):

An embodiment of the compound of Formula (VII.2)

wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, Cl₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R² is independently selected from the group consisting of        hydrogen, deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime        optionally substituted with C₁ alkyl;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, s alkyl optionally substituted with one or more,        identical or different, substituents R⁷ and —OC₃₋₅ cycloalkyl        optionally substituted with one or more, identical or different,        substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 275 is a compound according to any of embodiments 259-267,wherein the compound is an embodiment of Formula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of Cl and Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl each        of which may be optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R₈;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 276 is a compound according to any of embodiments 259-268,wherein the compound is an embodiment of Formula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl and C₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 277 is a compound according to any of embodiments 259-269,wherein the compound is an embodiment of Formula (VII.2), wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br, I;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₂₋₅ alkynyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each        of which is substituted with one or more, identical or        different, substituents R⁵; and    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁵ is independently selected from the group consisting of        deuterium, F, OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 278 is a compound according to any one of the precedingembodiments, wherein the compound is an embodiment of Formula (VII.2),wherein:

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₃₋₄ cycloalkyl        and —S—CH₃;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl, Br and I;    -   R³ is selected from the group consisting of fluoromethyl,        fluoroethyl and fluoropropyl, each of which may be optionally        substituted with one or more deuterium;    -   R⁴ is selected from the group consisting of H, C₁₋₅ alkyl        optionally substituted with one or more, identical or different,        substituents R⁷, C₃₋₆ cycloalkyl optionally substituted with one        or more, identical or different, substituents R⁷, phenyl        optionally substituted with one or more, identical or different,        substituents R⁸ and benzyl optionally substituted with one or        more, identical or different, substituents R⁸;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁸ is independently selected from the group consisting of        deuterium, methoxy, nitro, cyano, Cl, Br, I and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 279 is a compound according to any one of the precedingembodiments, wherein R⁴ is H.

Embodiment 280 is a compound according to any one of the precedingembodiments, wherein R⁴ is the sodium counterion.

Embodiment 281 is a compound according to any one of the precedingembodiments, wherein n is 0.

Embodiment 282 is a compound according to any one of the precedingembodiments, wherein n is 1.

Embodiment 283 is a compound according to any one of the precedingembodiments, wherein n is 2.

Embodiment 284 is a compound according to any one of the precedingembodiments, wherein

-   -   R¹ is selected from the group consisting of F, Cl, Br, I, —CN,        —CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and        —S—CH₃;    -   R³ is selected from the group consisting of C₁₋₅ alkyl, C₂₋₅        alkenyl, C₃₋₅ cycloalkyl and C₅ cycloalkenyl, each of which may        be optionally substituted with one or more F; and    -   R⁴ is selected from the group consisting of H and C₁₋₅ alkyl,        preferably H;    -   n is 0;    -   or a pharmaceutically acceptable salt, hydrate, polymorph,        tautomer, or solvate thereof.

Embodiment 285 is a compound according to embodiments 264, wherein R³ isselected from the group consisting of methyl, ethyl, n-propyl orisopropyl optionally substituted with one or more, identical ordifferent, substituents R⁵.

Embodiment 286 is a compound according to any one of the precedingembodiments, wherein R³ is methyl.

Embodiment 287 is a compound according to any one of the precedingembodiments, wherein R³ is ethyl.

Embodiment 288 is a compound according to any one of the precedingembodiments, wherein R¹ is selected from the group consisting of F, Cl,Br, and I.

Embodiment 289 is a compound according to any one of the precedingembodiments, wherein R¹ is selected from the group consisting of Cl andBr.

Embodiment 290 is a compound according to any one of the precedingembodiments, wherein R² is selected from the group consisting ofdeuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime optionally substitutedwith C₁ alkyl.

Embodiment 291 is a compound according to any one of the precedingembodiments, wherein R² is selected from the group consisting of F, Cland Br.

Embodiment 292 is a compound according to any one of the precedingembodiments, wherein R² is hydrogen or deuterium.

Embodiment 293 is a compound according to any one of the precedingembodiments wherein R¹ is Cl and R² is F.

Embodiment 294 is a compound according to any one of the precedingembodiments wherein R¹ is Cl and R² is Cl.

Embodiment 295 is a compound according to any one of the precedingembodiments wherein R¹ is Cl and R² is Br.

Embodiment 296 is a compound according to any one of the precedingembodiments wherein R¹ is Cl and R² is H.

Embodiment 297 is a compound according to any one of the precedingembodiments wherein R¹ is Cl and R² is D.

Embodiment 298 is a compound according to any one of the precedingembodiments wherein R¹ is Br and R² is F.

Embodiment 299 is a compound according to any one of the precedingembodiments wherein R¹ is Br and R² is C₁.

Embodiment 300 is a compound according to any one of the preceding theembodiments ms wherein R¹ is Br and R² is Br.

Embodiment 301 is a compound according to any one of the precedingembodiments wherein R¹ is Br and R² is H.

Embodiment 302 is a compound according to any one of the precedingembodiments wherein R¹ is Br and R² is D.

Embodiment 303 is a compound according to any one of the precedingembodiments, wherein R⁵ is independently selected from the groupconsisting of deuterium, F, —OC₁₋₅ alkyl optionally substituted with oneor more, identical or different, substituents R⁷ and —OC₃₋₅ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷.

Embodiment 304 is a compound according to any one of the precedingembodiments, wherein R⁶ is H.

Embodiment 305 is a compound according to any one of the precedingembodiments, wherein R⁶ is D.

Embodiment 306 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of C₁₋₃alkyl and C₃₋₄ cycloalkyl optionally substituted with one or more,identical or different, substituents R⁵.

Embodiment 307 is a compound according to any one of the precedingitems, wherein R³ is selected from the group consisting of C₁₋₃ alkyland C₃₋₄ cycloalkyl optionally substituted with one or more, identicalor different, substituents R⁵, with the proviso that when R¹ is Cl, R²is Cl, R⁴ is H, R⁶ is H, n is 0 and R³ is ethyl, then said ethyl issubstituted with one or more, identical or different, substituents R⁵.

Embodiment 308 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of methylsubstituted with one or more, identical or different, substituents R⁵,C₂₋₃ alkyl optionally substituted with one or more, identical ordifferent, substituents R⁵ and C₃₋₄ cycloalkyl optionally substitutedwith one or more, identical or different, substituents R⁵ with theproviso that when R¹ is Cl, R² is Cl, R⁴ is H, R⁶ is H, n is 0 and R³ isethyl, then said ethyl is substituted with one or more, identical ordifferent, substituents R⁵.

Embodiment 309 is a compound according to any one of the precedingembodiments, wherein R³ is methyl substituted with one or more,identical or different, substituents R⁵.

Embodiment 310 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of C₂₋₃alkyl and C₃₋₄ cycloalkyl optionally substituted with one or more,identical or different, substituents R⁵.

Embodiment 311 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting of C₂₋₃alkyl and C₃₋₄ cycloalkyl optionally substituted with one or more,identical or different, substituents R⁵, with the proviso that when R¹is Cl, R² is Cl, R⁴ is H, R⁶ is H, n is 0 and R³ is ethyl, then saidethyl is substituted with one or more, identical or different,substituents R⁵.

Embodiment 312 is a compound according to any one of the precedingembodiments, wherein R³ is ethyl optionally substituted with one ormore, identical or different, substituents R⁵ with the proviso that whenR¹ is Cl, R² is Cl, R⁴ is H, R⁶ is H, n is 0, and R³ is ethyl, then saidethyl is substituted with one or more, identical or different,substituents R⁵.

Embodiment 313 is a compound according to any one of the precedingembodiments, wherein R³ is n-propyl optionally substituted with one ormore, identical or different, substituents R⁵.

Embodiment 314 is a compound according to any one of the precedingembodiments, wherein R³ is isopropyl optionally substituted with one ormore, identical or different, substituents R⁵.

Embodiment 315 is a compound according to any one of the precedingembodiments, wherein R³ is cyclopropyl optionally substituted with oneor more, identical or different, substituents R⁵.

Embodiment 316 is a compound according to any one of the precedingembodiments, wherein R³ is cyclopropylmethyl optionally substituted withone or more, identical or different, substituents R⁵.

Embodiment 317 is a compound according to any one of the precedingembodiments, wherein R³ is cyclobutyl optionally substituted with one ormore, identical or different, substituents R⁵.

Embodiment 318 is a compound according to any one of the precedingembodiments, wherein R³ is substituted with one or more deuterium.

Embodiment 319 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting oftrideuteriomethyl, 1,2-dideuterioethyl and 1,1,2,2-tetradeuterioethyl.

Embodiment 320 is a compound according to any one of the precedingembodiments, wherein R³ is substituted with one fluorine.

Embodiment 321 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting offluoromethyl, fluoroethyl and fluoropropyl.

Embodiment 322 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting offluoromethyl, difluoromethyl, 2-fluoroeth-1-yl, (1S)-1-fluoroeth-1-yl,(1R)-1-fluoroeth-1-yl, (1S)-1,2-difluoroeth-1-yl,(1R)-1,2-difluoroeth-1-yl, 3-fluoroprop-1-yl, (1S)-1-fluoroprop-1-yl,(1R)-1-fluoroprop-1-yl, (2 S)-2-fluoroprop-1-yl, (2R)-2-fluoroprop-1-yl,(1S)-2-fluoro-1-methyl-eth-1-yl, (1S)-2-fluoro-1-methyl-eth-1-yl and2-fluoro-1-(fluoromethyl)eth-1-yl.

Embodiment 323 is a compound according to any one of the precedingembodiments, wherein R³ is selected from the group consisting offluoromethyl, 2-fluoroeth-1-yl, (1S)-1-fluoroeth-1-yl and(1R)-1-fluoroeth-1-yl.

Embodiment 324 is a compound according to any one of the precedingembodiments, wherein R³ is substituted with one or more —OC₁₋₅ alkylgroups optionally substituted with one or more, identical or different,substituents R⁷.

Embodiment 325 is a compound according to any one of the precedingembodiments, wherein R³ is substituted with one or more —OMe groupsoptionally substituted with one or more, identical or different,substituents R⁷.

Embodiment 326 is a compound according to any one of the precedingembodiments, wherein R³ is substituted with one or more —OEt groupsoptionally substituted with one or more, identical or different,substituents R⁷.

Embodiment 327 is a compound according to any one of the precedingembodiments, wherein R³ is substituted with one or more —OC₃₋₅cycloalkyl groups optionally substituted with one or more, identical ordifferent, substituents R⁷.

Embodiment 328 is a compound according to any one of the precedingembodiments, wherein R⁵ is independently selected from the groupconsisting of deuterium and F.

Embodiment 329 is a compound according to any one of the precedingembodiments, wherein R⁶ is H.

Embodiment 330 is a compound according to any one of the precedingembodiments, wherein R⁶ is D.

Embodiment 331 is a compound according to any one of the precedingembodiments, wherein:

-   -   R¹ is Cl;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, C₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

Embodiment 332 is a compound according to any one of the precedingembodiments, wherein:

-   -   R¹ is Cl;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0.

Embodiment 333 is a compound according to any one of the precedingembodiments, wherein:

-   -   R¹ is Cl;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

Embodiment 334 is a compound according to any one of the precedingembodiments, wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of F, Cl and Br;    -   R³ is methyl substituted with one or more, identical or        different, substituents R⁵, C₂₋₃ alkyl optionally substituted        with one or more, identical or different, substituents R⁵ or        C₃₋₄ cycloalkyl optionally substituted with one or more,        identical or different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

Embodiment 335 is a compound according to any one of the precedingembodiments, wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl substituted with one or more, identical or        different, substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is selected from the group consisting of hydrogen and        deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F; and    -   n is 0.

Embodiment 336 is a compound according to any one of the precedingembodiments, wherein:

-   -   R¹ is Br;    -   R² is selected from the group consisting of hydrogen, deuterium,        F, Cl and Br;    -   R³ is C₁₋₃ alkyl optionally substituted with one or more,        identical or different, substituents R⁵ or C₃₋₄ cycloalkyl        substituted with one or more, identical or different,        substituents R⁵;    -   R⁴ is H;    -   R⁵ is independently selected from the group consisting of        deuterium, F, —OC₁₋₅ alkyl optionally substituted with one or        more, identical or different, substituents R⁷ and —OC₃₋₅        cycloalkyl optionally substituted with one or more, identical or        different, substituents R⁷;    -   R⁶ is deuterium;    -   R⁷ is independently selected from the group consisting of        deuterium and F;    -   R⁹ is deuterium; and    -   n is 0, 1, 2 or 3.

Embodiment 337 is a compound for use according to any one of thepreceding embodiments, wherein the neuromuscular disorder is periodicparalysis, hyperkalemic periodic paralysis or hypokalemic periodicparalysis

EXAMPLES

Materials and Methods

Chemicals

Compounds for testing were obtained from different suppliers includingEnamine, Vitas, and CanAm Bioresearch. For synthesis of particularcompounds please see below.

General Synthetic Strategies

Compounds of Formula (I.2) may be synthesized by the following syntheticstrategies, general methods I-K:

NMR Spectra

¹H-NMR spectra were recorded on a Bruker AM-300 spectrometer and werecalibrated using residual nondeuterated solvent as internal reference.Spectra were processed using Spinworks version 4.0 (developed by Dr.Kirk Marat, Department of Chemistry, University of Manitoba), or on aBruker 400 MHZ Ultrashield plus equipped with probe BBO 400 MHz S1 5 mmwith Z gradient probe or a Bruker 500 MHz Avance III HD spectrometer,equipped with a Bruker 5 mm SmartProbe™, calibrated using residualnon-deuterated solvent as internal reference and spectra processed usingtopspin version 3.2.7.

HPLC Method 1

The product was analysed by Waters 2695 HPLC consisting of a Waters 996photodiode array detector, Kromasil Eternity C18, 5 μm, 4.6×150 mmcolumn. Flow rate: 1 mL/minute, run time 20 minutes. Solvent A:methanol; solvent B: 0.1% formic acid in water. Gradient 0-100% SolventB over 15 minutes with monitoring at 280 nm.

HPLC Method 2

Waters Acquity UPLC, X-Select; column: Waters X-Select UPLC C18, 1.7 μm,2.1×30 mm. Solvent A: 0.1% formic acid in water; solvent B: 0.1% formicacid in MeCN. Gradient 5-95% Solvent B over 10 minutes; detector: diodearray.

HPLC Method 3

Waters Acquity UPLC, X-Select; column: Waters X-Select UPLC C18, 1.7 μm,2.1×30 mm. Solvent A: 0.1% formic acid in water; solvent B: 0.1% formicacid in MeCN. Gradient 5-95% Solvent B over 3 minutes; detector: diodearray.

Statistics

All data are expressed as mean with SEM. Significant difference betweengroups was ascertained using a Students t-test (paired forcontra-lateral muscles). Statistical analysis was performed usingSigmaplot 12.0 including fitting of data (FIG. 4C, FIG. 5E, FIG. 6E) toa four parameter sigmoidal function to get Kd values for Tables 3-5.Categorical data was tested using Fishers Exact test. Groups wereconsidered significantly different for P-values <0.05.

Method A, Mitsunobu Coupling, Exemplified by(2S)-2-[(4-chloronaphthalen-1-yl)oxy]propanoic Acid

Procedure for Step A

To a solution of starting compound, Ph₃P, and ((R)-methyl2-hydroxypropanoate in a solvent like DCM was added DEAD at 0° C. Afterstirring for 1 to 24 h at room temperature, the reaction completion wasobserved by NMR testing of a sample. Aqueous workup was performed. Thecompound was purified by chromatography.

Procedure for Step C

To a solution of the product of Step A in ethanol was added an aqueoussolution of an alkali like KOH. The resulting mixture was refluxed for1-12 h, and reaction was monitored by TLC. At the end of reaction, themixture was subjected to an aqueous/acidic work up using a solvent likeDCM or an ether. The compound was purified by chromatography ifnecessary.

Method B, Displacement Coupling, Exemplified by(2S)-2-[(4-chlorophenyl)amino]propanoic Acid

Procedure for Step S

To a cold solution of pyridine in a solvent like DCM was addedtrifluoromethanesulfonic anhydride at below 0° C. After stirring for5-60 min, (R)-methyl 2-hydroxypropanoate was added. The mixture wasstirred for 1-10 h at room temperature, filtered, and the filtrate waspartially evaporated.

Procedure for Step T

To a mixture of 4-chloroaniline, a base like TEA and a solvent like DCMor DMF was added freshly prepared compound of step S at 0-5° C. Theresulting mixture was stirred at 35° C. for 4 h, diluted with water, andextracted with DCM when the phases do not separate. Removal of thesolvent yields the compound.

Procedure for Step C

See Step C in Method A above.

Method C, SN_(Ar) Displacement Coupling, Exemplified by(2S)-2-(4-bromophenoxy)-3-methylbutanoic Acid

Procedure for Step J

To a solution of acid amino acid in 1N H₂SO₄, a solution of NaNO₂ inminimal quantity of water was added under cooling. The resulted mixturewas stirred at room temperature for 1-3 days, saturated with Na₂SO₄, andextracted with a solvent like methyl-tert-butyl ether or DCM. Theorganic layer was evaporated.

Procedure for Step K

To a suspension of NaH in DMF a solution of the product of step J in DMFwas added. After stirring, p-fluoronitrobenzene or the desiredelectrophile was added and stirring continued at 100° C. for 3-48 h. Themixture was diluted a solution of NH₄Cl and K₂CO₃ at room temperature,and extracted with a solvent like methyl-tert-butyl ether or ethylacetate. The water layer was acidified with 3N HCl and extracted withmethyl-tert-butyl ether or ethyl acetate. The organic layer wasevaporated.

Procedure for Step L

To a 0° C. solution of the product of step K in methanol, a catalyticamount of acetyl chloride was added. The mixture was heated under refluxfor 3-9 h and the solvent was evaporated. The residue was extracted witha solvent like methyl-tert-butyl ether or DCM. The organic layer wasevaporated.

Procedure for Step M

To a solution of the product of step L in methanol, 10% Pd/C was addedand hydrogenated under ambient pressure for 24 h. The mixture wasfiltered through silica gel and evaporated.

Procedure for Step N

To a solution of t-BuNO₂ in acetonitrile, CuBr₂ was added. To thereaction mixture the product of step M in acetonitrile was added and themixture was heated under reflux for 2-9 h. To the room temperaturemixture, 20% aq. HCl was added and then extracted with a suitablesolvent like methyl-tert-butyl ether or ethyl acetate. The organic layerwas washed with water and evaporated. The oily residue waschromatographed.

Procedure for Step C

See Step C in Method A above.

Method D, Exemplified by 2-(4-fluorobenzenesulfonyl)propanoic Acid

Procedure for Step B

The thioether obtained by Method A or B in a suitable solvent like DCMor ethyl acetate is treated with m-CPBA or another peracid at roomtemperature for 1-48 h and the reaction is monitored by TLC. Afteraqueous workup, the product is purified by chromatography.

Method E, Exemplified by 3-amino-2-(4-fluorophenoxy)propanoic AcidHydrochloride

Procedure for Step A

See Step A in Method A above.

Procedure for Step C

See Step C in Method A above.

Procedure for Step D

The protected compound obtained from Step C in a suitable solvent likeDCM is treated with TFA at room temperature for 1-18 h. Afterevaporation, the product is purified by reversed-phase chromatographywith an HCl containing eluent.

Method F, Exemplified by 4-nitrophenyl (2S)-2-(4-chlorophenoxy)Propanoate

Procedure for Step E

The acid obtained by the previous methods in a suitable solvent like DCMor acetonitrile is treated DCC and the desired phenol, likep-nitrophenol, with a suitable catalyst like DMAP at room temperaturefor 1-48 h. After aqueous workup at acidic pH, the product is purifiedby rapid chromatography.

Method G, Exemplified by (2S)-2-(4-chlorophenoxy)propanal

Procedure for Step F

The ester obtained by the previous methods in a suitable solvent liketoluene is treated DIBAL-H at −78° C. for 1 h. After aqueous workup, theproduct is purified by rapid chromatography.

Method H, Exemplified by [[(2S)-2-(4chlorophenoxy)propylidene]amino]ethan-1-ol

Procedure for Step G

The aldehyde obtained by the step F in a suitable solvent like DCM istreated at room temperature with the desired primary amine like2-aminoethanol. Evaporation, redilution with DCM and re-evaporationyielded the desired product.

Compounds of Formula (I.2) May be Synthesized by the Following SyntheticStrategies, Methods I-K:

Method I involves the synthesis of Formula (X) (which is the same asFormula (I) in which R⁴ is H), which is an ether structure whenY=oxygen, and —R¹, —R² and —R³ are as defined in Formula (I) above.Compound (VII), in the case where Y═O is a phenol, is available eithercommercially or synthetically, and can be converted into an ether (IX)by methods which include Mitsunobu reaction conditions and compounds ofFormula (VIII). This ether contains an ester functionality —CO₂R⁶, whichcan be hydrolysed under a range of standard conditions, involving acidor base, to provide the carboxylic acid structure (X), Y═O. Thesestandard conditions can also for example involve an enzymic hydrolysis,employing for example an esterase or lipase. If an ester molecule (IX)includes for example a (CH₃)₃SiCH₂CH₂O— group as —OR⁶, then a fluorideion source such as tetra-n-butylammonium fluoride can be employed toconvert (IX) into the corresponding carboxylic acid (X). Some compoundscan optionally be tested without hydrolysis of the ester group, and inthis case R⁶ is equivalent to R⁴ as defined in Formula (I.2) above.

Substituted phenols of general formula (VII), Y═O, can be prepared by avariety of standard methods, for example by an ester rearrangement inthe Fries rearrangement, by a rearrangement of N-phenylhydroxylamines inthe Bamberger rearrangement, by hydrolysis of phenolic esters or ethers,by reduction of quinones, by replacement of an aromatic amine or by ahydroxyl group with water and sodium bisulfide in the Bucherer reaction.Other methods include hydrolysis of diazonium salts, by rearrangementreaction of dienones in the dienone phenol rearrangement, by theoxidation of aryl silanes, by the Hock process.

If a salt form of the product carboxylic acid is required, and alkalimetal salt, e.g. a sodium salt can be prepared utilizing for example oneequivalent of sodium hydroxide or sodium bicarbonate in aqueous solvent.This procedure also applies to Methods J and K.

Carboxylic acids of Formula (X) (which is the same as Formula (I) inwhich R⁴ is H), can also be prepared by the procedure illustrated asMethod J. A phenolic ether of Formula (IX) can be prepared bydisplacement of a suitable leaving group Q in (XI). Q can for example bea halogen such as fluorine or iodine, and the ether product of formula(IX) can be converted into the carboxylic acid derivative (X) by one ofa range of methods outlined in Method I, involving hydrolysis of theester functionality. Some compounds can optionally be tested withouthydrolysis of the ester group, and in this case R⁶ is equivalent to R⁴as defined in Formula (I.2) above.

Carboxylic acids of Formula (X) (which is the same as Formula (I) inwhich R⁴ is H), can be prepared by the procedure illustrated as MethodK. A phenolic ether of formula (XIV) can be prepared by utilising e.g.Mitsunobu conditions when (VII) is a phenol structure, i.e. Y═O, andXIII is a suitable secondary alcohol, i.e. Z═OH, and —R⁷ is a suitableprotecting group, such as a silyl-containing moiety. On removal of theprotecting group —R⁶ the primary alcohol (XV) can be oxidised to acarboxylic acid under standard conditions involving potassiumpermanganate, Jones oxidation conditions, the Heyns oxidation, rutheniumtetroxide or TEMPO.

Table B below illustrates Example compounds defined by Formula (I.2). Intable B, the HPLC System is one of the methods as defined in theMaterials and methods section.

SPECIFIC EXAMPLES OF SYNTHESES Example 1: Synthesis of(2R)-2-(4-bromophenoxy)-3-fluoropropanoic Acid; Following the SyntheticStrategy of Method K

(S)-1-(Benzyloxy)-3-fluoropropan-2-ol (1.2)

Tetrabutylammonium fluoride, 1M solution in THF (114 mL, 114 mmol) wasadded to a solution of (R)-2-((benzyloxy)methyl)oxirane (1.1) (15.56 g,95 mmol) in anhydrous toluene (300 mL, 95 mmol) and the mixture stirredat 80° C. under nitrogen for 24 h. The mixture was cooled to room temp.,diluted with water and extracted with ethyl acetate. The organic phasewas washed with brine, dried over MgSO₄ and evaporated in vacuo toafford a crude oil. The material was adsorbed onto silica then purifiedby chromatography on silica gel (220 g column, 0-100% EtOAc/isohexane)to afford (S)-1-(benzyloxy)-3-fluoropropan-2-ol (1.2) (6.419 g, 31.4mmol, 33% yield) as a pale yellow oil. The product was analysed by LCMS(Waters Acquity UPLC, C18, Waters X-Bridge UPLC C18, 1.7 μm, 2.1×30 mm,Acidic (0.1% Formic acid) 3 min method, 5-95% MeCN/water) 0.978 min, 91%purity @ 254 nm; ¹H NMR (400 MHz, CDCl₃) δ 7.43-7.30 (m, 5H); 4.59 (s,2H); 4.58-4.49 (m, 1H); 4.43 (qd, J=9.6, 4.9 Hz, 1H); 4.12-3.96 (m, 1H);3.67-3.54 (m, 2H); 2.52 (d, J=4.7 Hz, 1H).

(R)-1-((1-(Benzyloxy)-3-fluoropropan-2-yl)oxy)-4-bromobenzene (1.3)

To a solution of (S)-1-(benzyloxy)-3-fluoropropan-2-ol (1.2) (1.725 g,9.36 mmol), 4-bromophenol (1.62 g, 9.36 mmol) and triphenylphosphine(3.44 g, 13.11 mmol) in anhydrous THF (90 mL, 1098 mmol) at 0° C. wasadded DIAD (2.55 mL, 13.11 mmol). The solution was allowed to warm toroom temperature and stirred for 4 hours. After the allotted time, MeOHwas added and volatiles removed in vacuo. The crude product was purifiedby chromatography on silica gel (40 g column, 0-30% EtOAc/isohexane) toafford (R)-1-((1-(benzyloxy)-3-fluoropropan-2-yl)oxy)-4-bromobenzene(1.3) (998 mg, 2.80 mmol, 30% yield) as a clear colourless oil. Theproduct was analysed by LCMS (Waters Acquity UPLC, C18, Waters X-BridgeUPLC C18, 1.7 μm, 2.1×30 mm, Acidic (0.1% Formic acid) 3 min method,5-95% MeCN/water): m/z 339.822 (M+H)+ (ES+) at 1.858 min, 99% purity @254 nm. ¹H NMR (400 MHz, DMSO-d⁶) δ 7.45 (d, J=9.0 Hz, 2H); 7.37-7.25(m, 5H); 7.00 (d, J=9.0 Hz, 2H); 4.89-4.67 (m, 2H); 4.61 (qd, J=10.4,4.1 Hz, 1H), 4.53 (s, 2H); 3.73-3.62 (m, 2H).

(R)-2-(4-Bromophenoxy)-3-fluoropropan-1-ol (1.4)

Trichloroborane, 1M solution in dichloromethane (3.24 mL, 3.24 mmol) wasadded to a stirred solution of(R)-1-((1-(benzyloxy)-3-fluoropropan-2-yl)oxy)-4-bromobenzene (1.3) (998mg, 2.94 mmol) in anhydrous dichloromethane (45 mL, 699 mmol) undernitrogen at 0° C. After 2 hours the mixture was allowed to warm to roomtemperature, aqueous NaHCO₃ was added and the mixture stirred for 1 h atroom temperature. The phases were then separated and the aqueous furtherextracted with EtOAc. The combined organics were dried over MgSO₄ andvolatiles removed in vacuo to afford a pale yellow oil. The material wascarried forward without further purification.

(2R)-2-(4-Bromophenoxy)-3-fluoropropanoic Acid (1.5)

Sodium chlorite (1.342 g, 14.84 mmol) was dissolved in 1M sodiumphosphate buffer pH6 (60 mL, 60.0 mmol) and added to a solution of(R)-2-(4-bromophenoxy)-3-fluoropropan-1-ol (2.843 g, 7.42 mmol) (1.4) inacetonitrile (60 mL), followed by aqueous sodium hypochlorite solution(0.087 mL, 0.074 mmol) and TEMPO (0.041 g, 0.260 mmol). The resulting2-phase mixture was stirred at room temp for 1 hour. Further aqueoussodium hypochlorite solution (0.087 mL, 0.074 mmol) and TEMPO (0.041 g,0.260 mmol) were added and the mixture was stirred overnight at roomtemperature. Further aqueous sodium hypochlorite solution (0.27 mL,0.222 mmol) and TEMPO (0.123 g, 0.780 mmol) were added and the reactionstirred for a further 3 h. To the mixture was added saturated sodiummetabisulfite solution (40 mL) and the mixture was diluted with water,acidified by addition of conc. hydrochloric acid and extracted withethyl acetate. The organic phase was extracted with aq. sodium hydroxidesolution (1 M). The aqueous phase was acidified to pH 2, by addition ofconc. hydrochloric acid, then extracted with ethyl acetate. The combinedorganic extracts were dried over MgSO₄ and volatiles removed in vacuo.The material was adsorbed onto silica then purified by chromatography onsilica gel (80 g column, 0-50% EtOAc/isohexane) to afford(R)-2-(4-bromophenoxy)-3-fluoropropanoic acid (1.5) (1.307 g, 4.72 mmol,63% yield) as a colourless solid. The product was analysed by LCMS(Agilent Infinity, X-Select, Waters X-Select C18, 2.5 μm, 4.6×30 mm,Acidic (0.1% Formic acid) 15 min method, 5-95% MeCN/water): (M+H)+(ES+); 260.900 (M−H)− (ES−), at 4.166 min, 95% purity @ 254 nm. (Note:product has poor absorption at 254 nm). ¹H NMR (400 MHz, DMSO-d⁶) δ13.53 (s, 1H); 7.46 (d, J=9.0 Hz, 2H); 6.93 (d, J=9.0 Hz, 2H); 5.20(ddd, J=29.1, 3.9, 2.5 Hz, 1H); 4.97-4.71 (m, 2H).

To a solution of (R)-2-(4-bromophenoxy)-3-fluoropropanoic acid (1.5)(867 mg, 3.30 mmol) in acetonitrile (23 mL) was added sodium bicarbonate(277 mg, 3.30 mmol) in H₂O (8 mL) and the reaction stirred at ambienttemperature for 30 min. After the allotted time, volatiles were removedin vacuo and excess water removed by co-evaporation with toluene,resulting in a clear oil. Dichloromethane was added and removedresulting in a colourless solid. The solid was triturated with furtherdichloromethane and dried in a dessicator overnight to afford sodium(R)-2-(4-bromophenoxy)-3-fluoro-propanoate (1.6) (0.496 g, 1.65 mmol,50%). The colourless solid product was analysed by LCMS (AgilentInfinity, X-Select, Waters X-Select C18, 2.5 μm, 4.6×30 mm, Acidic (0.1%Formic acid) 15 min method, 5-95% MeCN/water): (ES+); 260.976 (M−Na)−(ES−), at 1.476 min, 95% purity @ 254 nm. ¹H NMR (400 MHz, DMSO-d⁶) δ7.36 (d, J=9.0 Hz, 2H); 6.78 (d, J=9.0 Hz, 2H); 4.86-4.53 (m, 2H); 4.47(ddd, J=23.5, 7.5, 2.2 Hz, 1H).

Example 2: (2S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutanoic Acid,Adapted From Method I

(S)-2-(4-bromo-2-fluorophenoxy)-3-methyl)butanoic Acid (2.2)

DIAD (2.343 mL, 12.05 mmol) was added to a stirred solution of(R)-tert-butyl 2-hydroxy-3-methylbutanoate (2.1) (1.5 g, 8.61 mmol),4-bromo-2-fluorophenol (1.037 mL, 9.47 mmol) and triphenylphosphine(3.16 g, 12.05 mmol) in anhydrous tetrahydrofuran (50.6 mL, 8.61 mmol)at 0° C. and stirred for 30 min before being allowed to warm to roomtemperature. After 16 hours, the mixture was evaporated in vacuo to asyrup which was re-dissolved in formic acid (33.0 mL, 861 mmol) andheated to 70° C. for 1 hour. MeOH (20 mL) was added and the resultingsolution was evaporated in vacuo and the residue co-evaporated withtoluene (2×30 mL). The residue was dissolved in ethyl acetate (100 mL)and extracted with 0.5M sodium hydroxide solution (100 mL). The aqueousphase was washed with ethyl acetate (2×100 mL) then acidified to pH 2-3by dropwise addition of c. hydrochloric acid. The resulting cloudysolution was extracted with ethyl acetate (3×100 mL). Organic extractswere filtered through a phase separating funnel. The residue waspurified by column chromatography (40 g Grace silica cartridge) with0-40% ethyl acetate in isohexane gradient elution to give an oil whichwas dried in vacuo at 40° C. overnight to give(S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutanoic acid (2.2) (1.6436 g,5.53 mmol, 64.3% yield) as a white waxy solid.

The product was analysed by LCMS (Waters Acquity UPLC, X-Select, WatersX-Select UPLC C18, 1.7 μm, 2.1×30 mm, Acidic (0.1% Formic acid) 10 minmethod, 5-95% MeCN/water): m/z 289-291 (M−H)− (ES−), at 4.352 min, 97.6%purity @ 254 nm; ¹H NMR (400 MHz, DMSO-d⁶) δ 13.16 (s, 1H), 7.53 (dd,J=10.9, 2.4 Hz, 1H), 7.34-7.27 (m, 1H), 6.97 (t, J=9.0 Hz, 1H), 4.61 (d,J=4.6 Hz, 1H), 2.31-2.18 (m, 1H), 1.01 (dd, J=6.5 Hz, 6H).

To (S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutanoic acid (2.2) (0.8254g, 2.77 mmol) in MeCN (27 mL) was added NaHCO₃ (0.232 g, 2.77 mmol) inH₂O (9 mL) and the mixture was stirred at room temperature for 30 min.The aqueous solvent was removed under reduced pressure to give a whitesolid which was dissolved in H₂O (30 mL) and washed with DCM (3×30 mL).The water was removed under reduced pressure and the residue dried at45° C. in vacuo for 72 hours to give sodium(S)-2-(4-bromo-2-fluorophenoxy)-3-methylbutanoate (2.3) (0.866 g, 2.63mmol, 95% yield) as a white solid. The product was analysed by LCMS(Waters Acquity UPLC, X-Select, Waters X-Select UPLC C18, 1.7 μm, 2.1×30mm, Acidic (0.1% Formic acid) 10 min method, 5-95% MeCN/water): m/z288.915, 290.966 (M−H)− (ES−), 89% purity @ 254 nm. 100% purity @210-400 nm. (Poor absorbance @254). 1H NMR (400 MHz, DMSO-d6) δ 7.39(dd, J=11.0, 2.4 Hz, 1H), 7.18 (ddd, J=8.8, 2.5, 1.5 Hz, 1H), 6.86 (t,J=9.0 Hz, 1H), 3.92 (d, J=5.0 Hz, 1H), 2.21-2.08 (m, 1H), 0.95 (d, J=6.7Hz, 6H).

In conclusions, this example demonstrates that compound 4.4 can beprepared using the synthetic strategy herein.

TABLE A Synthesis of compounds Compounds of formula (I) may besynthesized by one of Synthetic Methods A to H, as shown in the below.Exam- Prepa- ple ration number IUPAC name method NMR C1 (2S)-2-(4- A1H-NMR (400 MHz, chlorophenoxy) DMSO-d6): δ 13.2 (s, propanoic acid 1H),7.35 (m, 2H), 6.9 (m, 2H), 4.85 (q, 1H), 1.45 (d, 3H). C2(2S)-2-[(4-chloro- B 1H-NMR (500 MHz, phenyl)amino]pro- DMSO-d6): δ 7.15(m, panoic acid 2H), 6.58 (m, 2H), 3.95 (q, 1H), 1.35 (d, 3H). C32-(benzyloxy)pro- B 1H-NMR (400 MHz, panoic acid CDCl₃): δ 9.8 (s, 1H),7.35 (m, 5H), 4.7 (d, 1H), 4.5 (d, 1H), 4.05 (q, 1H), 1.47 (d, 3H). C42-(4-fluorophenoxy) A 1H-NMR (400 MHz, propanoic acid DMSO-d6): δ 12.68(s, 1H), 6.9 (m, 4H), 4.68 (q, 1H), 1.62 (d, 3H). C5(2S)-2-(benzyloxy)pro- B 1H-NMR (400 MHz, panoic acid CDCl₃): δ 11.3(bs, 1H), 7.4 (m, 5H), 4.71 (d, 1H), 4.52 (d, 1H), 4.08 (q, 1H), 1.47(d, 3H). C6 2-(4-fluorobenzene D 1H-NMR (500 MHz, sulfonyl)propanoicDMSO-d6): δ 13.4 (s, acid 1H), 7.96 (m, 2H), 7.51 (m, 2H), 4.38 (q, 1H),1.35 (d, 3H). C7 2-(4-chloro- A 1H-NMR (400 MHz, phenoxy)butanoicDMSO-d6): δ 12.72 (bs, acid 1H), 7.23 (m, 2H), 6.83 (m, 2H), 4.52 (m,1H), 1.9 (m, 2H), 1.05 (m, 3H). C8 (2S)-2-(4-bromo- A 1H-NMR (300 MHz,phenoxy)propanoic CDCl₃): δ 8.42 (bs, 1H), acid 7.35 (m, 2H), 6.78 (m,2H), 4.71 (q, 1H), 1.62 (d, 3H). C9 3-amino-2-(4- E 1H-NMR (400 MHz,fluorophenoxy) DMSO-d6): δ 13.7 (bs, propanoic acid 1H), 8.25 (s, 2H),7.18 hydrochloride (m, 2H), 7.02 (m, 2H), 5.05 (q, 1H), 3.15 (bs, 2H).C10 (2S)-2-[(4- A 1H-NMR (400 MHz, chloronaphthalen-1- DMSO-d6): δ 13.2(bs, yl)oxy]propanoic 1H), 8.25 (d, 1H), 8.0 (d, acid 1H), 7.6 (m, 3H),6.90 (d, 1H), 4.98 (q, 1H), 1.58 (d, 3H). C11 4-chlorophenyl F 1H-NMR(300 MHz, 2-(4-chlorophenoxy) DMSO/CCl₄): δ 7.41 (m, propanoate 2H),7.08 (m, 6H), 5.14 (m, 1H), 1.71 (d, 3H). C12 (2S)-2-(5-bromo- C 1H-NMR(300 MHz, CDCl₃): pyrimidin-2-yl)-3- δ 9.65 (bs, 1H), 8.42methylbutanoic (m, 2H), 5.05 (dd, 1H), acid 2.44 (m, 1H), 1.2 (m, 6H).C13 2-[(1S)-1-(4- H 1H-NMR (300 MHz, chlorophenoxy)ethyl]- CDCl₃): δ7.24 (m, 2H), 1,3-oxazolidine 6.9 (m, 2H), 4.62 (m, 1H), 4.41 (m, 1H),3.8 (m, 2H), 3.3 (m, 1H), 3.1 (m, 1H), 1.4 (m, 3H). C142-(4-bromophenoxy)- B 1H-NMR (500 MHz, 2-cyclopropylactic DMSO-d6): δ13.1 (s, acid 1H), 7.48 (m, 2H), 6.8 (m, 2H), 4.08 (d, 1H), 1.12 (m,1H),0.5 (m, 4H). C15 2-(4-bromophenoxy)- B 1H-NMR (500 MHz,3acetamidopropanoic DMSO-d6): δ 13.3 (s, acid 1H), 8.15 (s, 1H), 7.48(m, 2H), 6.85 (m, 2H), 4.70 (q, 1H), 3.61 (m, 1H), 3.31 (m, 1H), 1.72(s, 3H). C16 2-(4-bromophenoxy)- B 1H-NMR (500 MHz, 3-methane- DMSO-d6):δ 13.4 (bs, sulfonamidopro- 1H), 7.5 (m, 3H), 6.92 panoic acid (m, 2H),4.85 (m, 1H), 3.52 (m, 1H), 3.35 (m, 1H) 2.9 (s, 3H). C17 (2S)-2-(4- G1H-NMR (300 MHz, chlorophenoxy) CDCl3): δ 9.7 (d, 1H), propanal 7.25 (m,2H), 6.81 (m, 2H), 4.61 (q, 1H), 1.45 (m, 3H). C18 4-nitrophenyl F1H-NMR (300 MHz, (2S)-2-(4- CDCl₃): δ 8.28 (m, 2H), chlorophenoxy) 7.25(m, 4H), 6.84 (m, propanoate 2H), 5.02 (m, 1H), 1.82 (m, 3H). C194-methoxyphenyl F 1H-NMR (300 MHz, (2S)-2-(4- CDCl₃): δ 7.3 (m, 2H),chlorophenoxy) 6.92 (m, 6H), 4.9 (q, 1H), propanoate 3.81 (s, 3H), 1.78(dd, 3H). C20 2-(4-bromophenoxy)- B 1H-NMR (400 MHz, 2-(3-ethoxycyclo-DMSO-d6): δ 13.1 (bs, butyl)acetic acid 1H), 7.42 (m, 2H), 6.81 (m, 2H),4.65 (dd, 1H), 3.44 (m, 1H), 3.30 (m, 1H), 3.24 (m, 3H), 2.36 (m, 1H),0.9 (dd, 3H). C21 2-(4-bromophenoxy)- B 1H-NMR (400 MHz, 4-methoxy-3-DMSO-d6): δ 13.1 (s, methylbutanoic 1H), 7.42 (m, 2H), 6.82 acid (m,2H), 4.61 (d, 1H), 3.80 (m, 1H), 3.28 (m, 2H), 2.31 (m, 3H), 1.80 (m, 2H), 1.05 (t, 3H). C22 (2S)-2-(4- A 1H-NMR (500 MHz, bromophenoxy)-CDCl₃): δ 7.41 (m, 2H), 3methylbutanoic 6.78 (m, 2H), 4.41 (d, acid 1H),2.38 (q, 1H), 1.11 (d, 6H).

Table B below illustrates Example compounds defined by the generalFormula (I.3.4). In table B, the HPLC System is one of the methods asdefined in the Materials and methods section.

TABLE B Illustrative Examples of the Invention Compound HPLC SynthesisNumber IUPAC name ¹H NMR retention time method A-1 (2R)-2-[4-bromo(3,5-1H NMR (500 MHz, 2.911 (2) K ²H₂)phenoxy]-3- DMSO-d6) δ 13.53 (s,fluoropropanoic acid 1H), 6.92 (s, 2H), 5.19 (ddd, J = 29.2, 4.1, 2.4Hz, 1H). 4.95-4.74 (m, 2H). A-2 (2S)-2-[4-bromo(3,5- 1H NMR (500 MHz,3.036 (2) I ²H₂)phenoxy]propanoic DMSO-d6) δ 13.08 (s, acid 1H), 6.85(s, 2H), 4.84 (q, J = 6.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H). A-3 ethyl(2S)-2-(4-bromo-2- 1H NMR (300 MHz, 13.499 (1) I fluorophenoxy)-3-CDCl3) δ 7.29-7.13 (m, methylbut-3-enoate 2H), 5.21 (d, 1H), 5.04 (s,1H), 1.88 (s, 3H), 1.28 (t, 3H). A-4 (2R)-2-(4-bromo-2- 1H NMR (500 MHz,4.358 (2) I fluoraphenoxy)-3- DMSO-d6) δ 13.15 (s, methylbutanoic acid1H), 7.54 (dd, J = 10.9, 2.4 Hz. 1H), 7.31 (ddd, J = 8.8, 2.4, 1.5 Hz,1H), 6.98 (t, J = 9.0 Hz, 1H), 4.62 (d, J = 4.6 Hz, 1H), 2.25 (pd, J =6.8, 4.5 Hz. 1H), 1.03 (d, J = 6.9 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H).A-5 (2R)-2-[4-bromo(2,6- 1H NMR (500 MHz, 2.852 (2) K ²H₂)phenoxy]-3-DMSO-d6) δ 13.54 (s, fluoropropanoic acid 1H), 7.46 (s, 2H), 5.17 (d, J= 28.7 Hz, 1H). 4.96- 4.75 (m, 2H). A-6 (2S)-2-[4-bromo(2,6- 1H NMR (400MHz, 3.028 (2) I ²H₂)phenoxy]propanoic DMSO-d6) δ 13.17(s, acid 1H),7.44 (s, 2H), 4.88- 4.76 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H). A-7(2S)-2-(4- 1H NMR (400 MHz, 2.970 (2) K bromophenoxy)-3- DMSO-d6) δ13.53 (s, fluoropropanoic acid 1H), 7.51-7.41 (m, 2H), 6.97-6.88 (m,2H), 5.20 (ddd, J = 29.2, 4.0, 2.5 Hz, 1H), 4.96-4.72 (m, 2H). A-8(2S)-2-(4-bromo-2- ¹H NMR (300 MHz, 14.547 (1) I iodophenoxy)propanoicCDCl₃) δ 10.38-9.28 (br, acid 1H); 7.93 (d, 1H); 7.39 (dd, 1H); 6.63 (d,1H); 4,78 (q, 1H); 1.75 (d, 3H). A-9 (2R)-2-(4-bromo-2- 1H NMR (400 MHz,3.424 (2) K fluorophenoxy)-3,3- DMSO-d6) δ 7.58 (dd, J =difluoropropanoic acid 10.8, 2.4 Hz, 1H), 7.36- 7.29 (m, 1H), 7.13 (t, J= 9.0 Hz, 1H), 6.51 (td, J = 53.1, 2.1 Hz, 1H), 5.30 (dd, J = 20.1, 7.9Hz, 1H). A-10 (2S)-2-{4-bromo-2-[(1E)- 1H NMR (300 MHz, 14.473 (1) I(methoxyimino)methyl]phe- CDCl3) δ 7.40 (d, 1H), noxy}propanoic acid4.80 (q, 1H), 3.99 (s, 3H), 1.69 (d, 3H). A-11 (2S)-2-(2-bromo-4- 1H NMR(300 MHz, 15.404 (1) I chlorophenoxy)-3- CDCl3) δ 6.68 (d, 1H),methylbutanoic acid 4.48 (d, 1H), 2.41 (m, 1H), 1.18 (d, 3H), 1.16 (d,3H); A-12 (2S)-2-(2-fluoro-4- 1H-NMR (300 MHz, 13.629 (1) Iiodophenoxy)propanoic CDCl3): 10.50-10.12 (br, acid 1H), 7.40 (dd, 2H),4.79 (q, 1H), 1.69 (d, 3H). A-13 (2S)-2-(2-bromo-4- 1H-NMR (300 MHz,14.713 (1) I iodophenoxy)propanoic CDCl3): δ 10.48-10.09 acid (br, 1H),7.88 (s, 1H), 4.79 (q, 1H), 1.73 (d, 3H). A-14 ethyl 2-(4-bromo-2- 1HNMR (300 MHz, 18.077 (1) I fluorophenoxy)-3,3,3- CDCl3) δ 6.99 (t, 1H),trifluoropropanoate 4.94 (q, 1H), 4.41-4.29 (m, 2H), 1.32 (t, 3H). A-15ethyl 2-(4- 1H NMR (300 MHz, 17.92 (1) I bromophenoxy)-3,3,3- CDCl3) δ7.48-7.40 (m, trifluoropropanoate 2H), 4.93 (q, 1H), 4.40- 4.30 (m, 2H),1.31 (t, 3H). A-16 (2S)-2-(2-chloro-4- 1H-NMR (300 MHz, 14.52 (1)8 Iiodophenoxy)propanoic CDCl3): δ 10.38-10.19 acid (br, 1H), 7.72 (s, 1H),4.79 (q, 1H), 1.73 (d, 3H). A-17 (2S)-2-(2-bromo-4- 1H NMR (300 MHz,14.188 (1) I chlorophenoxy)propanoic MeOD) δ 6.90 (d, 1H), acid 4.85 (m,1H), 1.64 (d, 3H); A-18 2-(4-bromophenoxy)-2- ¹H NMR (300 MHz, 15.452(1) I cyclopentylacetic acid CDCl₃) δ 9.93-9.27 (br, 1H); 7.38 (d, 2H);6.79 (d, 2H); 4.47 (d, 1H); 2.58- 2.40 (m, 1H); 1.94-1.44 (m, 8H). A-19(2R)-2-(4-bromo-2- 1H NMR (400 MHz, 3.109 (2) K fluorophenoxy)-3-DMSO-d6) δ 7.58 (dd, J = fluoropropanoic acid 10.9, 2.4 Hz, 1H), 7.33(ddd, J = 8.8, 2.4, 1.5 Hz, 1H), 7.11 (t, J = 9.0 Hz, 1H), 5.30 (ddd, J= 29.3, 3.9, 2.4 Hz, 1H), 5.02- 4.77 (m, 2H). A-20 (2S)-2-(4-chloro-2-1H NMR (400 MHz, 4.148 (2) I fluorophenoxy)-3- DMSO-d6) δ 13.19 (s,methylbutanoic acid 1H), 7.44 (dd, J = 11.1, 2.6 Hz, 1H), 7.19 (ddd, J =8.9, 2.6, 1.6 Hz, 1H), 7.03 (t, J = 9.0 Hz, 1H), 4.62 (d, J = 4.6 Hz,1H), 2.25 (pd, J = 6.9, 4.6 Hz, 1H), 1.02 (app dd, J = 6.8, 6.0 Hz, 6H).A-21 (2R)-2-(2-bromo-4- 1H NMR (400 MHz. 1.936 (2) K chlorophenoxy)-3-DMSO-d6) δ 13.71 (s, fluoropropanoic acid 1H), 7.73 (d, J = 2.6 Hz, 1H),7.40 (dd, J = 8.9, 2.6 Hz, 1H), 7.07 (d, J = 8.9 Hz, 1H), 5.32 (ddd, J =29.1, 4.0, 2.4 Hz, 1H), 5.00-4.77 (m, 2H). A-22 (2R)-2-(4- 1H NMR (400MHz, 1.088 (2) K chlorophenoxy)-3- DMSO-d6) δ 13.47 (s, fluoropropanoicacid 1H), 7.38-7.30 (m, 2H), 7.02-6.93 (m, 2H), 5.20 (ddd, J = 29.1,3.9, 2.5 Hz, 1H), 4.97-4.72 (m, 2H). A-23 (2R)-2-(4-chloro-2- 1H NMR(400 MHz, 1.188 (2) K fluorophenoxy)-3- DMSO-d6) δ 13.60 (s,fluoropropanoic acid 1H), 7.47 (dd, J = 11.2, 2.4 Hz, 1H), 7.21 (ddd, J= 8.9, 2.4, 1.0 Hz, 1H), 7,16 (t, J = 8.8 Hz, 1H), 5.30 (ddd, J = 29.3,3.9, 2.4 Hz, 1H), 5.03-4.70 (m, 2H). A-24 (2R)-2-(2,4- 1H NMR (400 MHz,2.041 (2) K dibromophenoxy)-3- DMSO-d6) δ 13.63 (s, fluoropropanoic acid1H), 7.83 (d, J = 2.4 Hz, 1H), 7.52 (dd, J = 8.8, 2.4 Hz, 1H), 7.01 (d,J = 8.9 Hz, 1H), 5.32 (ddd, J = 29.0, 3.9, 2.4 Hz, 1H), 5.02-4.76 (m,2H). A-25 (2S)-2-(4- 1H NMR (400 MHz, 0.942 (2) I bromophenoxy)-3-DMSO-d6) δ 7.47-7.41 hydroxypropanoic acid (m, 2H), 6.90-6.83 (m, 2H),4.74 (dd, J = 5.1, 3.8 Hz, 1H), 3.86-3.78 (m, 2H). A-26 (2R)-2-(4- 1HNMR (400 MHz, 2.913 (2) K bromophenoxy)-3- DMSO-d6) δ 13.51 (s,fluoropropanoic acid 1H), 7.49-7.43 (m, 2H), 6.96-6.89 (m, 2H), 5.24-5.12 (m, 1H), 4.95-4.75 (m, 2H). A-27 (2S)-2-(4-bromo-2- 1H NMR (400MHz, 4.343 (2) I fluorophenoxy)-3- DMSO-d6) δ 13.19 (s, methylbutanoicacid 1H), 7.54 (dd, J = 10.9, 2.4 Hz, 1H), 7.31 (ddd, J = 8.9, 2.4, 1.5Hz, 1H), 6.98 (t, J = 9.0 Hz, 1H), 4.61 (d, J = 4.5 Hz, 1H), 2.31-2.20(m, 1H), 1.02 (app dd, J = 6.9, 6.0 Hz, 6H). A-28 (2R)-2-(4-bromo-2- 1HNMR (400 MHz, 3.207 (2) I fluorophenoxy)propanoic DMSO-d6) δ 13.21 (s,acid 1H), 7.55 (dd, J = 10.9, 2.4 Hz, 1H), 7.31 (ddd, J = 8.8, 2.4, 1.5Hz, 1H), 7.00 (t, J = 9.0 Hz, 1H), 4.95 (q, J = 6.8 Hz, 1H), 1.53 (d, J= 6.8 Hz, 3H). A-29 (2R)-2-(4-chloro- 1H NMR (400 MHz, 2.825 (2) Iphenoxy)propanoic DMSO-d6) δ 13.10 (s, acid 1H), 7.38-7.26 (m, 2H),6.94-6.84 (m, 2H), 4.84 (q, J = 6.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H).A-30 (2S)-2-(3-bromo-4- 1H NMR (400 MHz, 3.683 (2) Ichlorophenoxy)propanoic DMSO-d6) δ 13.16 (s, acid 1H), 7.52 (d, J = 8.9Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H), 6.95 (dd, J = 8.9, 3.0 Hz, 1H), 4.96(q, J = 6.7 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H). A-31 (2S)-2-(4-bromo-2-1H NMR (Chloroform-d, 1.283 (3) I fluorophenoxy)propanoic 400 MHz) δ7.29 (0.5H, d, acid J = 2.3 Hz), 7.26 (0.5H, d, J = 2.3 Hz), 7.19 (0.5H,dd, J = 2.3, 1.6 Hz), 7.17 (0.5H, dd, J = 2.3, 1.6 Hz), 6.85 (1H, t, J =8.7 Hz), 4.78 (1H, q, J = 6.9 Hz), 1.69 (3H, d, J = 6.9 Hz) A-32(2S)-2-[4-(tri- 1H NMR (400 MHz, 1.302 (3) I fluoromethyl)phe- CDCl₃) δ7.56 (2H, d, noxy]propanoic acid J = 8.5 Hz), 6.96 (2H, d, J = 8.5 Hz),4.86 (1H, q, J = 6.9 Hz), 1.70 (3H, d, J = 6.9 Hz) A-33 sodium(2S)-2-(4- 1H-NMR (300 MHz, 15.797 (1) I chlorophenoxy)-5- CD₃OD): δ7.18 (d, 2H), methylhexanoate 4.29 (t, 1H), 1.97-1.84 (m, 2H), 0.93 (d,6H). A-34 methyl (2S)-2-(4- 1H-NMR (300 MHz, 16.382 (1) Ichlorophenoxy)-5- CDCl3): δ 7.23 (d, 2H), methylhexanoate 4.56 (t, 1H),3.76 (s, 3H), 1.68-1.51 (m, 1H), 1.49- 1.26 (m, 2H), 0.93 (d, 6H). A-35sodium (2S)-2-(4- 1H NMR (300 MHz, 15.306 (1) I chlorophenoxy)-4- CDCl3)δ 6.84 (d, 2H), methylpentanoate 4.68-4.59 (m, 1H), 1.01 (d, 3H), 0.95(d, 3H); A-36 sodium (2S)-2-(4- 1H NMR (300 MHz, 15.39 (1) Ichlorophenoxy)hexanoic CD3OD) δ 7.17 (d, 2H), acid 4.31 (t, 1H), 1.88(q, 2H), 1.60-1.30 (m, 4H), 0.92 (t, 3H). A-37 methyl (2S)-2-(4- 1H NMR(300 MHz, 16.07 (1) I chlorophenoxy)hexanoate CDCl3) δ 6.82 (d, 2H),4.57 (t, 1H), 3.75 (s, 3H), 1.95 (m, 2H), 0.93 (t, 3H). A-38(2S)-2-(4-chloro-2- 1H NMR (400 MHz, 3.04 (2) I fluorophenoxy)propanoicDMSO-d6) δ 13.15 (s, acid 1H), 7.45 (dd, J = 11.2, 2.6 Hz, 1H), 7.19(ddd, J = 8.8, 2.5, 1.5 Hz, 1H), 7.06 (t, J = 9.0 Hz, 1H), 4.95 (q, J =6.8 Hz, 1H), 1.53 (d, J = 6.8 Hz, 3H). A-39 (2S)-2-(3,4-dichloro- 1H NMR(400 MHz, 7.59 (2) I phenoxy)propanoic DMSO-d6) δ 13.16 (s, acid 1H),7.53 (d, J = 9.0 Hz, 1H), 7.18 (d, J = 2.9 Hz, 1H), 6.92 (dd, J = 9.0,2.9 Hz, 1H), 4.96 (q, J = 6.8 Hz, 1H), 1.50 (d, J = 6.8 Hz, 3H). A-40(2S)-2-(2,4-dibromo- 1H NMR (400 MHz, 1.451 (3) I phenoxy)propanoicCDCl₃) δ 7.71 (1H, d, acid J = 2.4 Hz), 7.36 (1H, dd, J = 8.7, 2.4 Hz),6.75 (1H, d, J = 8.8 Hz), 4.78 (1H, q, J = 6.9 Hz), 1.72 (3H, d, J = 6.9Hz) A-41 (2S)-2-[4-(prop-1-yn-1- 1H NMR (300 MHz, 12.97 (1) Iyl)phenoxy]propanoic CD₃OD) δ 7.25 (d, 2H), acid 4.77 (q, 1H), 1.98 (s,3H), 1.57 (d, 3H). A-42 (2S)-2-(4-- ethynyl- 1H-NMR (300 MHz, 11.175 (1)I phenoxy)propanoic CD3OD): δ 7.31 (d, 2H), acid 4.49 (q, 1H), 1.52 (d,3H). A-43 sodium (2S)-2-(4- 1H NMR (300 MHz, 13.299 (1) Ichlorophenoxy)butanoate CD3OD) δ 6.87 (d, 2H), 4.28 (t, 1H), 1.07 (t,3H); A-44 sodium (2S)-2-(2,4- 1H-NMR (300 MHz, 13.564 (1) Idichlorophenoxy)propanoate CD3OD): δ 7.35 (s, 1H), 6.86 (d, 1H), 4.44(q, 1H), 1.58 (d, 3H). A-45 sodium (2S)-2-(4- 1H-NMR (300 MHz, 9.686 (1)I chlorophenoxy)-3- CD3OD): δ 7.16 (d, 2H), methylbutanoate 4.05 (q,1H), 2.26-2.09 (m, 1H), 1.04 (dd, 6H). A-46 sodium (2S)-2-(4- 1H NMR(300 MHz, 12.937 (1) I ethylphenoxy)propanoate CD3OD) δ 6.81 (d, 2H),4.47 (q, 1H), 2.54 (q, 2H), 1.51 (d, 3H), 1.17 (t, 3H); A-47 sodium(2S)-2-(4- 1H NMR (300 MHz, 10.35 (1) I cyanophenoxy)propanoate CD3OD) δ7.00 (d, 2H), 4.58 (q, 1H), 1.57 (d, 3H); A-48 sodium (2S)-2-[4- 1H NMR(300 MHz, 5.858 (1) I (methylsulfanyl)phe- CD3OD) δ 6.85 (d, 2H),noxy]propanoate 4.47, (q, 1H), 2.39 (s, 3H), 1.52 (d, 3H); A-49 methyl(2S)-2-(4- 1H NMR (300 MHz, 11.73 (1) I ethynylphenoxy)propanoate CDCl3)δ 7.42 (d, 2H), 4.78 (q, 1H), 3.76 (s, 3H), 3.01 (s, 1H), 1.67 (d, 3H).A-50 methyl (2S)-2-(4- 1H NMR (300 MHz, 15.11 (1) Ibromophenoxy)propanoate CDCl3) δ 7.38 (d, 2H), 4.73 (q, 1H), 3.76 (s,3H), 1.63 (d, 3H). A-51 methyl (2S)-2-(4- 1H NMR (300 MHz, 12.98 (1) Ichlorophenoxy)butanoate CDCl3) δ 7.24 (d, 2H), 4.54 (t, 1H), 3.76 (s,3H), 1.99 (m, 2H), 1.07 (t, 3H). A-52 2,2,2-trifluoroethyl (2S)- 1H NMR(300 MHz, 13.279 (1) I 2-(4-chlorophenoxy)pro- CDCl3) δ 7.25 (m, 2H),panoate 4.84 (q, 1H), 4.56 (q, 2H), 1.67 (d, 3H). A-53 propan-2-yl(2S)-2-(4- 1H NMR (300 MHz, 13.595 (1) I chlorophenoxy)propanoate CDCl3)δ 7.23 (m, 2H), 5.07 (m, 1H), 4.67 (q, 1H), 1.61 (d, 3H), 1.27 (d, 3H).A-54 methyl (2S)-2-(4-chloro- 1H NMR (300 MHz, 14.969 (1) Iphenoxy)propanoate CDCl3) δ 7.20 (d, 2H), 4.70 (q, 1H), 3.78 (s, 3H),1.65 (d, 3H). A-55 (2S)-2-(4-bromo-2,6- 1H NMR (400 MHz, 4.444 (2) Idifluorophenoxy)-3- DMSO-d6) δ 13.11 (s, methylbutanoic acid 1H),7.55-7.42 (m, 2H), 4.58 (dt, J = 4.5, 1.2 Hz, 1H), 2.21 (pd, J = 6.8,4.5 Hz, 1H), 1.03 (d, J = 6.8 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H). A-56(2S)-2-(4-bromo- ¹H NMR (300 MHz, 14.016 (1) I phenoxy)butanoic CDCl₃) δ10.21-9.28 (br, acid 1H); 7.39 (d, 2H); 6.79 (d, 2H); 4.58 (t, 1H); 2.03(q, 2H); 1.11 (t, 3H). A-57 (2S)-2-(4-cyclo- 1H NMR (300 MHz, 14.623 (1)I butylphenoxy)propanoic CDCl3) δ 11.19 (br s, 1H), acid 7.16 (d, 2H),4.78 (q, 1H), 3.57-3.43 (m, 1H), 1.67 (d, 3H). A-58 (2S)-2-(4-bromo-2-1H NMR (300 MHz, 14.177 (1) I fluorophenoxy)butanoic CDCl3) δ 10.68 (brs, 1H), acid 6.85 (t, 1H), 4.61 (m, 1H), 2.06 (m, 2H), 1.13 (t, 3H).A-59 (2S,3E)-2-(4- 1H NMR (300 MHz, 9.836 (1) I bromophenoxy)-4- CDCl3)δ 7.40 (d, 2H), fluorobut-3-enoic acid 6.14-5.97 (m, 0.5 H), 5.69-5.55(m, 1H), 5.45 (d, 0.5H). A-60 (2S)-2-(4- 1H NMR (400 MHz, 3.895 (2) Ibromophenoxy)(2- DMSO-d6) δ 7.35- ²H)butanoic acid 7.28 (d, J = 8.5 Hz,2H), 6.77-6.70 (d, JU = 8.5 Hz, 2H), 1.83- 1.66 (m, 2H), 0.93 (t, J =7.4 Hz, 3H). A-61 (2S)-2-(4- 1H NMR (300 MHz, 9.962 (1) Ibromophenoxy)pent- CDCl3) δ 7.99-7.48 (br, 4-ynoic acid 1H), 7.41 (d,2H), 4.78 (t, 1 H), 2.13 (s, 1H). A-62 (2S)-2-(4-bromo-2- 1H NMR (300MHz, 11.552 (1) I fluorophenoxy)pentanoic CD3OD) δ 7.25 (d, 1H), acid7.16 (d, 1H), 4.35 (t, 1 H), 2.03- 1.69-1.44 (m, 2H), 0.98 (t, 3H). A-63(2S)-2-(2,4-dibromo- 1H NMR (300 MHz, 12.621 (1) I phenoxy)pentanoicCD3OD) δ 7.64 (s, 1H), acid 6.77 (d, 1H), 4.37-4.27 (m, 1H), 0.98 (t,3H); A-64 (2S)-2-(4-bromo-2- 1H-NMR (300 MHz, 12.324 (1) Ichlorophenoxy)pentanoic CD3OD): δ 7.44 (d, acid 1H), 7.26 (d, 1H), 4.28(dd, 1H), 2.0-1.78 (m, 2H), 1.69-1.44 (m, 2H), 0.94 (t, 3H). A-65(2S)-2-(4- 1H NMR (300 MHz, 12.16 (1) I bromophenoxy)-3- CDCl3) δ10.75-10.32 cyclopropylpropanoic (br, 1H), 7.40 (d, 2H), acid 4.71 (t,1H), 2.07-1.93 (m, 1H), 1.89-1.74 (m, 1H), 0.28-0.09 (m, 2H). A-66(2S)-2-(2,4- 1H NMR (300 MHz, 11.909 (1) I dibromophenoxy)pent- CDCl3) δ7.73 (s, 1H), 4-ynoic acid 6.87 (d, 1H), 4.82 (t, 1H), 2.15 (s, 1H);A-67 (2S)-2-(4-bromo-2- 1H-NMR (300 MHz, 10.83 (1) I chlorophenoxy)pent-CD3OD): δ 9.73-8.96 4-ynoic acid (br, 1H), 7.55 (s, 1H), 7.33 (d, 1H),4.81 (t, 1H), 2.98 (d, 2H), 2.15 (s, 1H). A-68 (2S)-2-(4- 1H NMR (300MHz, 10.358 (1) I bromophenoxy)-2- CD3OD) δ 7.31 (d, 2H),cyclopropylacetic acid 6.81 (d, 2H), 3.86 (d, 1 H), 1.45-1.21 (m, 1H),0.72-0.37 (m, 4H). A-69 (2S)-2-(4-bromo-2- 1H NMR (300 MHz, 10.91 (1) Ifluorophenoxy)pent- CDCl3) δ 9.39-8.42 (br, 4-ynoic acid 1H), 7.29 (d,1H), 7.21 (d, 1H), 4.81 (t, 1H), 2.94 (d, 2H), 2.14 (s, 1H). A-70(2S)-2-(4-bromo- 1H-NMR (300 MHz, 14.589 (1) I phenoxy)pentanoic CD3OD):δ 7.18 (d, acid 2H), 4.20 (t, 1H), 1.81- 1.65 (m, 2H), 1.53-1.27 (m,2H), 0.82 (t, 3H). A-71 (2S)-2-(4-bromo-2- 1H NMR (300 MHz, 12.735 (1) Ichlorophenoxy)-2- CDCl3) δ 10.54-9.99 cyclobutylacetic acid (br, 1H),7.54 (d, 1H), 7.29 (dd, 1 H), 4.55 (d, 1H), 3.07-2.87 (m, 1H), 2.34-1.76(m, 6H). A-72 (2S)-2-(4-bromo-2- 1H NMR (300 MHz, 13.104 (1) Ichlorophenoxy)-3- CD3OD) δ 7.55 (s, 1H), cyclopropylpropanoic 6.86 (d,1H), 4.80 (t, acid 1H), 1.11-0.93 (m, 1H), 0.61-0.41 (m, 2H); A-73(2S)-2-(4-bromo-2- 1H NMR (500 MHz, 2.378 (2) I chlorophenoxy)-3-DMSO-d6) δ 7.92 (d, J = methylbutanoic acid 2.4 Hz, 1H), 7.34 (dd, J =8.9, 2.5 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 3.87 (d, J = 4.8 Hz, 1H),2.27-2.08 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.97 (d, J = 6.8 Hz, 3H)A-74 (2S)-2-(2,4- 1H NMR (300 MHz, 10.51 (1) I dibromophenoxy)-3- CDCl3)δ 7.71 (d, 1H), methoxypropanoic 7.37 (dd, 1 H), 6.24- acid 5.16 (br,1H), 4.83 (t, 1H), 3.51 (s, 3H). A-75 (2S)-2-(4- 1H NMR (300 MHz, 10.051(1) I bromophenoxy)but-3- CDCl3) δ 8.16-7.54 (br, enoic acid 1H), 7.40(d, 2H), 6.14- 5.98 (m, 1H), 5.47 (d, 1H), 5.14 (d, 1H). A-76 (2S)-2-(4-1H NMR (300 MHz, 10.499 (1) I bromophenoxy)(3,4- CD3OD) δ 7.34 (d, 2H),²H₂)butanoic acid 4.41 (d, 1H), 2.02-1.83 (m, 1H), 1.04 (d, 2H). A-77(2R)-2-(4-bromo-2- 1H NMR (500 MHz, 3.657 (2) I chlorophenoxy)-3-DMSO-d6) δ 7.58 (d, J = fluoropropanoic acid 2.5 Hz, 1H), 7.37 (dd, J =8.9, 2.5 Hz, 1H), 6.83 (d, J = 8.9 Hz, 1H), 4.78 (ddd, J = 47.7, 10.2,2.2 Hz, 1H), 4.69 (ddd, J = 49.3, 10.2, 7.6 Hz, 1H), 4.54 (ddd, J =23.3, 7.6, 2.2 Hz, 1H). A-78 (2S)-2-(4-bromo-2- 1H NMR (500 MHz, 1.874(2) I chlorophenoxy)butanoic DMSO-d6) δ 7.55 (d, J = acid 2.5 Hz, 1H);7.35 (dd, J = 8.8, 2.5 Hz, 1H); 6.80 (d, J = 8.9 Hz, 1H); 4.07 (dd, J =7.7, 4.5 Hz, 1H); 1.95-1.60 (m, 2H); 0.97 (t, J = 7.4 Hz, 3H). A-79(2S)-2-(4-bromo-3- 1H NMR (300 MHz, 11.551 (1) I fluorophenoxy)-3-CDCl3) δ 9.94-9.50 (br, methylbutanoic acid 1H), 7.42 (t, 1H), 6.61 (dd,1 H), 4.41 (d, 1H), 2.44-2.25 (m, 1H), 1.11 (d, 6H). A-80(2S)-2-(4-bromo-2- 1H-NMR (300 MHz, 11.811 (1) I chlorophenoxy)-4-CD3OD): δ 7.45 (d, fluorobutanoic acid 1H), 7.28 (dd, 1H), 4.81-4.63 (m,1H), 4.64-4.48 (m, 1H), 2.45-2.05 (m, 2H). A-81 (2S)-2-(4-bromo-2,3- 1HNMR (300 MHz, 12.541 (1) I difluorophenoxy)-3- CDCl3) δ 9.88 (s, 1H),methylbutanoic acid 6.59 (t, 1H), 4.43 (d, 1H), 1.09 (t, 6H); A-82(2R)-2-(4- 1H NMR (500 MHz, 2.955 (2) I bromophenoxy)-3- DMSO-d6) δ13.53 (s, fluoro(2-²H)propanoic 1H), 7.54-7.34 (m, acid 2H), 6.99-6.85(m, 2H), 4.87 (dd, J = 46.9, 10.5 Hz, 1H), 4.83 (dd, J = 47.8, 10.4 Hz,1H). A-83 (2S)-2-(4-bromo-2- 1H-NMR (300 MHz, 15.038 (1) Iiodophenoxy)-4- CD3OD): δ 9.67-8.38 fluorobutanoic acid (br, 1H), 7.92(d, 1H), 7.41 (dd, 1H), 4.94- 4.80 (m, 2H), 2.62-2.29 (m, 2H). A-84(2S)-2-(4- 1H NMR (300 MHz, 12.88 (1) I bromophenoxy)-2- CDCl3) δ10.0-8.66 (br, cyclobutylacetic acid 1H), 7.39 (d, 2H), 4.51 (d, 1H),2.24-1.80 (m, 6H). A-85 (2S)-2-(4-bromo-2- 1H NMR (300 MHz, 11.56 (1) Ifluorophenoxy)-4- CDCl3) δ 11.18-10.40 fluorobutanoic acid (br, 1H),7.28 (dd, 1H), 7.19 (dd, 1 H), 4.92- 4.64 (t, 1H), 2.56-2.20 (m, 2H).A-86 (2S)-2-(4-bromo-2- 1H NMR (300 MHz, 15.117 (1) I fluorophenoxy)-2-CD3OD) δ 7.26 (dd, cyclobutylacetic acid 1H), 7.16 (d, 1 H), 4.26 (d,1H), 2.99-2.83 (m, 1H), 2.31-1.74 (m, 6H). A-87 (2S)-2-(4- 1H-NMR (300MHz, 10.955 (1) I bromophenoxy)-4- CD3OD): δ 7.33 (d, fluorobutanoicacid 2H), 4.70 (t, 1H), 4.59- 4.44 (m, 2H), 2.44-2.06 (m, 2H). A-88(2S)-2-(4-bromo-2- 1H NMR (500 MHz, 5.194 (2) I iodophenoxy)-3-Chloroform-d) δ 7.91 methylbutanoic acid (d, J = 2.4 Hz, 1H), 7.36 (dd,J = 8.7, 2.4 Hz, 1H), 6.51 (d, J = 8.7 Hz, 1H), 4.48 (d, J = 4.2 Hz,1H), 2.40 (heptd, J = 6.9, 4.3 Hz, 1H), 1.20 (d, J = 6.9 Hz, 3H), 1.18(d, J = 6.9 Hz, 3H). A-89 (2S)-2-(4-bromo-2- 1H NMR (500 MHz, 3.826 (1)I fluorophenoxy)-2- DMSO-d6) δ 13.13 (s, cyclopropylacetic acid 1H),7.55 (dd, J = 10.9, 2.4 Hz, 1H), 7.31 (ddd, J = 8.8, 2.5, 1.5 Hz, 1H),6.92 (t, J = 9.0 Hz, 1H), 4.26 (d, J = 8.4 Hz, 1H), 1.36- 1.27 (m, 1H),0.69-0.46 (m, 4H). (N.B. free acid) A-90 (2S)-2-(4-bromo-2- 1H-NMR (300MHz, 15.25 (1) I iodophenoxy)butanoic CDCl3): δ 7.93 (d, 1H), acid 7.39(dd, 1H), 4.67 (t, 1H), 3.35 (s, 1H), 2.11 (q, 2H), 1.16 (t, 3H). A-91(2S)-2-(4-chloro-2- 1H NMR (300 MHz, 13.821 (1) I fluorophenoxy)butanoicCDCl3) δ 9.14-7.91 (br, acid 1H), 7.14 (dd, 1H), 7.04 (dq, 1 H), 4.62(t, 1H), 2.15-1.99 (m, 2H), 1.14 (t, 3H). A-92 (2S)-2-cyclopropyl-2- 1HNMR (400 MHz, 4.863 (2) I (2,4-dibromophenoxy)acetic DMSO-d6) δ 7.68 (s,acid 1H), 7.37 (s, 1H), 6.74 (d, J = 9.0 Hz, 1H), 3.81 (s, 1H), 1.26 (s,1H), 0.48 (d, J = 28.9 Hz, 4H) A-93 (2S)-2-(4-bromo-2- 1H NMR (400 MHz,4.708 (2) I chlorophenoxy)-2- DMSO-d6) δ 7.55 (d, J = cyclopropylaceticacid 2.5 Hz, 1H), 7.33 (dd, J = 8.8, 2.5 Hz, 1H), 6.78 (d, J = 8.9 Hz,1H), 3.76 (d, J = 6.9 Hz, 1H), 1.33-1.13 (m, 1H), 0.56-0.33 (m, 4H).A-94 (2R,3R)-2-(4- 1H NMR (400 MHz, 3.675 (2) I bromophenoxy)-3-DMSO-d6) δ 7.40- fluorobutanoic acid 7.30 (m, 2H), 6.85- 6.75 (m, 2H),4.92 (dp, J = 49.1, 6.3 Hz, 1H), 4.05 (dd, J = 22.4, 5.7 Hz, 1H), 1.33(dd, J = 23.9, 6.4 Hz, 3H). A-95 (2R,3R)-2-(4-bromo- 1H NMR (400 MHz,3.886 (2) I 2-fluorophenoxy)-3- DMSO-d6) δ 7.44 (dd, fluorobutanoic acidJ = 11.0, 2.4 Hz, 1H), 7.22 (ddd, J = 8.8, 2.5, 1.5 Hz, 1H), 6.91 (t, J= 9.0 Hz, 1H), 4.99 (dqd, J = 48.6, 6.4, 5.3 Hz, 1H), 4.14 (dd, J =23.5, 5.3Hz, 1H), 1.35 (dd, J = 23.9, 6.4 Hz, 3H).

Description of Pharmacological Methods and Drawings

Isolation of Muscles from Rats and Human, Ethical Approval, Dissectionof Muscles, Solutions, and Chemicals

Experiments were performed using rat soleus muscles from either young(4-wk-old) or adult Wistar rats (12-14-week-old). Animal handling,killing and isolation of muscle is described elsewhere All experimentswere performed using normal Krebs-Ringer bicarbonate solution (NKR). Insolutions with elevated Mg²⁺, MgCl₂ was added to NKR-solution causingminor increases in osmolarity and ionic strength. In solutions withelevated K⁺, 4 mM NaCl was replaced by 4 mM KCl in the NKR.

For experiments conducted using human abdominal muscle, details onpatients, approval and the approaches for isolation, transportation, andexperimentation are available elsewhere

Electrical Stimulation, Contractile Force and M-Waves

In all contraction experiments, isometric force production wasdetermined and force produced during contractions was quantified bymeasuring the integral of the force response (AUC). Stimulation andforce recordings have been described elsewhere. Briefly, muscles werestimulated to contract in three different ways (FIG. 1 ): i) When usingfield stimulation (25-30 V/cm) and pulses with a duration of 0.2 ms, themuscles could be stimulated directly without requirements of afunctional motor nerve. ii) If the duration of the pulses used in thefield stimulation was only 0.02 ms, the contractile force could becompletely suppressed by the nicotinic ACh receptor antagonisttubocurarine. This shows that stimulation with short pulses activatesthe muscles indirectly through stimulation of the attached motor nerve.iii) Stimulation could be isolated to the motor nerve after it had beensucked into a glass capillary. In these latter experiments,extracellular recordings of action potentials (M-waves) could bemeasured without temporal overlap with stimulation artefacts.

Cable Properties and Endplate Potentials

Isolated soleus muscles from adult rats or human abdominal musclespreparations were placed in a chamber and the resting membraneconductance (G_(m)) was measured in individual fibers usingelectrophysiological techniques described in detail elsewhere (FIG. 4 ).G_(m) reflects function of ion channels that are open at the restingmembrane potential. In skeletal muscle, G_(m) is dominated by CIC-1 Cl⁻channels and for this reason an effect of a compound on G_(m)predominantly reflects alterations in CIC-1 function. To ensure that thecompound indeed affected CIC-1 function, recordings were in some casesrepeated in the presence of the CIC-1 inhibitor 9-AC (100 μM) toquantify for effects of the compounds on K⁺ channels. To determineaffinity of CIC-1 channels for a particular compound, G_(m) was plottedagainst compound concentration and a Boltzmann sigmoidal function wasfitted to the data to obtain Kd of the compound (Table 3).

To measure endplate potentials (EPPs), soleus muscles from adult ratswere placed in a chamber and the motor nerve was stimulated. To onlymeasure EPPs, 1 μM of μ-conotoxin GiiiB was added to solution. Allrecordings were corrected for variation in resting membrane potentialusing −80 mV as the standard

Pharmacokinetic Analysis and Test of C₈ in Rat Models of MyastheniaGravis

The pharmacokinetic analysis of a single, intraperitoneal (I.P.) dose ofC8 (10 mg/kg) was studied in young (4 weeks old) Sprague-Dawley rats.This part of the study was performed by Pipeline Biotech A/S (Spørring,Denmark). 24 animals were injected with C8 and three animals weresacrificed at times 15 min, 30 min, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 24 hrafter injection and plasma concentrations of C8 was determined usingLiquid Chromatography Mass Spectrometry (LC-MS). Plasma concentrations(free and bound) were determined by OnTarget Chemistry (Uppsala, Sweden,Project No.: PB243-001).

Two sets of in vivo experiments were performed with C8: In the firstseries of experiments I.P. tubocurarine at (0.13 mg/kg) was used toinduce a myasthenia like phenotype while in the second series ofexperiments a passive immunization model of myasthenia gravis was usedin which rats were injected I.P. with a monoclonal antibody against theacetylcholine receptors at the neuromuscular endplate (MAB35, GTX14187,Genetex, 0.4-0.6 mg/kg). In both series of experiments, runningperformance was tested on a rotarod using a protocol where the rod wasaccelerated gradually over a 5 min period, and the running time andcovered distance before falling off the rod were measured. To accustomthe animals to the rotarod, the animals were tested three times on twoconsecutive days and animals that failed to complete the 5 min ofrunning on the last day of familiarization period were not used inexperiments. Experiments with tubocurarine were carried out over twodays, and on each day the effect of tubocurarine on running performancewas tested. On the first day only tubocurarine was injected. Animalsthat failed to respond to tubocurarine were not used on the next day ofexperimentation. On the second day, the animals were first allowed torun on the rotarod, and all animals performed normally. This shows thateffects of the tubocurarine that had been injected on the day before hadcompletely disappeared. Animals were then divided into two groups: Onegroup was injected with 20 mg/kg C8 while the other group received shamtreatment. 2 hrs after the C8 or sham injection, the second injection oftubocurarine was administered and the animals running performance on therotarod was tested. The allocation of the animals into the two groups(C₈ or sham) was random and unknown to the experimenter (blindedexperimental design).

In experiments with MAB35, animals were first familiarized with therotarod over two consecutive days and then injected I.P. with MAB35.After injection, rotarod performance was then again monitored regularlyover the consecutive two days. Performance generally started to declinewithin 21-43 hrs after MAB35 injection, and if a stable reduction inperformance was obtained, the animals were administered either C8 orsham. A considerable number of animals, however, became moribund failingto walk and they had altered ventilation (rapid) and pronounced ptosis.These animals were not included in experiments. Animals with a stablereduction in performance were injected with C8 (20 or 30 mg/kg) or shamtreated and their performance were again monitored 2, 4, and 6 hrs afterC8 or sham injection.

Example 3: Experimental Approach for Testing Compounds

The aim was to find compounds that by inhibition of CIC-1 channels canrecover nerve-stimulated force under conditions of fatigue includingconditions where fatigue is caused by compromised neuromusculartransmission. Neuromuscular transmission dysfunction can develop becauseof both pre- and/or post-synaptic complications in connection with adisorder or as part of neuromuscular blockade during/after surgery. Inthe initial series of drug testing, experiments were performed withisolated muscles in the presence of sub-maximal ACh receptor antagonisttubocurarine. Since the inclusion of tubocurarine caused a partial lossof neuromuscular transmission this experiment mimics the conditions inmyasthenia gravis and neuromuscular blockade. To mimic conditions withpre-synaptic complication (Lambert Eaton syndrome, motor neurondisorder, polyneuropathy) the intact nerve-muscle preparations wereincubated at elevated extracellular Mg²⁺, which is known to suppressrelease of ACh from nerve terminals of motor neurons.

Experiments shown in FIG. 1 were performed to confirm that tubocurarineand elevated extracellular Mg²⁺ specifically suppressed neuromusculartransmission without affecting the capacity of the muscle fibers togenerate force. The experiments also illustrate that field stimulationof the entire nerve-muscle preparation selectively activates the motornerve when short-duration pulses (0.02 vs 0.2 ms) were used. In FIG. 1Athe preparation was stimulated either via field stimulation or vianerve-stimulation using a suction electrode. With the suction electrodeonly the nerve could be stimulated. When exposed to a submaximalconcentration of the ACh receptor antagonist tubocurarine (0.2 μM) aclear drop in peak force and a further decline (or fade) in force duringthe stimulation developed. This drop in force clearly reflectedcompromised neuromuscular transmission, as the decline in peak force andfading were not seen with direct stimulation of the muscle. Recordingsof M-waves in the muscle in FIG. 1A show that tubocurarine caused markeddecline in M-wave signal during the stimulation (compare inserts i andii in FIG. 1A). Thus, loss of M-wave and force with tubocurarinereflected partial blockade of neuromuscular function. Such fading offorce and M-waves during stimulation represent clinical hallmarks ofboth myasthenia gravis and neuromuscular blockade in connection withsurgery. In FIG. 1B, observations with normal (0.2 ms) andshort-duration (0.02 ms) pulses have been compared. It can be seen thatonly with short-duration pulses did tubocurarine cause a decline in peakforce and fading (FIG. 1B). This confirms that short-duration pulses infield stimulation could be used as specific nerve-stimulation. FIG. 10shows that also elevated extracellular Mg²⁺ primarily affectednerve-stimulated force while it did not affect force when the muscle wasstimulated directly. Elevated extracellular Mg²⁺ could thus be used topartially block neuromuscular transmission and thus be used as a modelof conditions with compromised pre-synaptic function (Lambert Eatonsyndrome, amyotrophic lateral sclerosis, spinal muscular atrophy).

Example 4: Proof-of-Concept that CIC-1 Inhibition can Overcome Loss ofNeuromuscular Transmission in Conditions Mimicking NeuromuscularDisorders

To initially confirm that inhibition of CIC-1 ion channels can be usedto recover contractile force in muscle with reduced neuromusculartransmission, isolated nerve-muscle preparations were first exposed toeither tubocurarine (FIG. 2A) or elevated Mg²⁺ (FIG. 2B) and then aspecific CIC-1 inhibitor (9-AC) was added. It can be seen that CIC-1inhibition caused a marked recovery of both force and M-wave signal inboth conditions. This demonstrates the novel concept that CIC-1 channelinhibition can alleviate loss of force induced by compromisedneuromuscular transmission. Similar observations were seen in EDL anddiaphragm muscles from both young and adult rats (data not shown). 9-ACdoes not have the potential to be used as a pharmaceutical.

Example 5: Identification of Useful Compounds for ImprovingNeuromuscular Transmission

To identify CIC-1 inhibitors that could be used for treatment ofneuromuscular disorders we repeated the experiment shown in FIG. 2A butinstead of adding 9-AC we added the compounds of interest in differentconcentrations within the range from 10 to 500 μM. The starting pointfor finding CIC-1 inhibitors was derivatives of clofibrate that havebeen shown to have CIC-1 inhibiting actions (Table 1). FIG. 3A showsrepresentative nerve-stimulated force in two muscles during such anexperiment before and during exposure to tubocurarine. In one of themuscles (black trace), 50 μM of a test compound (C8) was added after 40mins in tubocurarine. For comparison with the muscle only exposed totubocurarine (grey trace), the two traces have been overlaid. It can beseen that while tubocurarine affected the two muscles equally before C8addition (middle traces), the muscle receiving C8 recovered markedlywhen compared to its force before C8 addition and especially whencompared to the other muscle that did not get C8 (right traces). Toquantify the recovery of force with compounds such as C8, the forceintegrals (AUC) were determined for each contraction during anexperiment and these AUC values were related to AUC before addition oftubocurarine. FIG. 3B shows average AUC observations of force duringexperiments in which muscles at tubocurarine were exposed to C8. Forcomparison, muscles only exposed to tubocurarine have been included. Thedotted line indicates the recovery of force with C8 when compared to theforce production before its addition. This value was used in Table 1 forevaluation of the efficacy of the different compounds in recoveringforce. Please note that force produced by the muscles only exposed totubocurarine continued to fall after C8 had been added to the othergroup of muscles. This shows that C8 is able to recover force despite aprogressively stronger suppressive action of tubocurarine.

TABLE 1 Recovery of nerve-stimulated force by some compounds in isolatedrat soleus muscles exposed to sub-maximal tubocurarine concentration.AUC force was first determined after 40 min in tubocurarine (column 3)and related to nerve-stimulated force prior to addition of tubocurarine.The AUC at the different concentrations of compounds (columns 4-6) isthe % change in AUC compared to the AUC before addition (column 3).Force before 50 μM % 150 μM % 500 μM % addition of change change changecompound % after after after IUPAC of control addition addition additionn C5 (2S)-2- 24 −7 1 42 2 (benzyloxy)propanoic acid C6 2-(4- 39 −11 −8 9 5 fluorobenzenesulfonyl) propanoic acid C7 2-(4- 41 −12 0 40 2chlorophenoxy)butanoic acid C8 (2S)-2-(4- 36 16 23 NT 10bromophenoxy)propanoic acid C9 3-amino-2-(4- 57 −14 −13  5 2fluorophenoxy)propanoic acid hydrochloride C11 4- chlorophenyl 2- (4- 3846 54 NT 4 fluorophenoxy)propanoate C21 2-(4-bromophenoxy)- 54 −3 7 36 24-methoxy-3- methylbutanoic acid C22 (2S)-2-(4- 42 16 NT NT 2bromophenoxy)- 3methylbutanoic acid NT: Not Tested

In a separate series of experiments with 8 isolated rat soleus muscles,ACh receptors were inhibited using 2 μM rocuronium, which is aclinically used neuromuscular blocking agent. Under these conditions thenerve-stimulated force was reduced to 51±5% of force before rocuronium.When 50 μM C₈ was subsequently added nerve-stimulated contractile forcewas significantly recovered to 81±4% of force before rocuronium(p<0.01). This illustrates the potential of these compounds to be usedas reversal agents.

The next series of experiments determined whether the compounds thatrecovered nerve-stimulated force in the presence of tubocurarine couldalso recover nerve-stimulated force at elevated extracellular Mg²⁺. Todo this the experiment depicted in FIG. 2B was repeated with C8. As inFIG. 3 , AUC was quantified for each contraction and the capacity of C8to recover force at elevated Mg²⁺ was evaluated from the recovery of AUCcompared to AUC immediately before application of the compound (Table2).

TABLE 2 Recovery of nerve-stimulated force with compounds in isolatedrat soleus muscles exposed to 3.5 mM Mg²⁺. AUC force was firstdetermined after 70 min at elevated extracellular Mg²⁺ (column 3) andrelated to nerve-stimulated force prior to addition of additional Mg²⁺.The AUC at the different concentrations of compounds (columns 4 and 5)is the % change in AUC compared to the AUC before Mg²⁺ elevation (column3). As in experiments with tubocurarine, please note that force keptdropping in muscles only exposed to elevated Mg²⁺. Force before additionof 50 μM 100 μM compound % change % change % of after after IUPACcontrol addition addition n C8 (2S)-2-(4-bromo- 38 ± 6 13 ± 4 26 ± 5 2phenoxy)propanoic acid

Example 6: Effect of Compounds on CIC-1 Channels—Target Validation

The effect of compounds on CIC-1 ion channels was determined in musclefrom adult rats using electrophysiological techniques describedelsewhere. With this technique, three electrodes were placed in the samemuscle fiber and by injecting small current pulses through twoelectrodes it was possible to obtain the voltage responses to thiscurrent injection at three inter-electrode distances. Examples ofvoltage responses at the three inter-electrode distances in a controlfiber and in a fiber at 10 μM C₈ are presented in FIG. 4A. By plottingthe steady state deflection of the voltage responses againstinter-electrode distance, G_(m) can be determined from fits of the datato a two-parameter exponential function (FIG. 4B). The lines connectingdata points in FIG. 4B show fits of data to the two-parameterexponential function. Such recordings were performed for relevantcompounds for a range of compound concentrations, and in FIG. 4C theobservations of G_(m) at the different concentrations of C8 have beenplotted. A Kd for a particular compound was obtained by fitting the dataof G_(m) in FIG. 4C to a sigmoidal function (line in FIG. 4C). Such Kdvalues have been included in Table 3 for relevant compounds. Theobservations in Table 3 show that compounds that were particulareffective in recovering nerve-stimulated force in muscle withcompromised neuromuscular transmission (Tables 1 and 2) were also potentinhibitors of G_(m) (Table 3).

Also included are Kd values for compounds when tested in human muscleusing an approach identical to that in rat muscle.

TABLE 3 Effect of different compounds on G_(m) in isolated rat and humanmuscles. G_(m) No Kd for ClC-1 Compound inhibition C8 Rat 642 ± 25, n =33  9 μM C8 Human 430 ± 41, n = 5  5.5 μM C22 rat 642 ± 25, n = 33 4.1μM

Example 7: Combination Treatments

CIC-1 is a novel target in treatment of neuromuscular complications andit was therefore explored whether this approach for symptomatictreatment could be used in combination with existing symptomatictreatment approaches. In myasthenia gravis, which in isolated muscleswas mimicked by tubocurarine, the symptoms of muscle fatigue are mostcommonly treated with inhibitors of acethylcholineesterase of whichneostigmine and pyridostigmine are examples. Also, neostigmine is themost commonly used reversal agent of neuromuscular blocked aftersurgery. To test if CIC-1 inhibitors and neostigmine or pyridsostigminecan be used in combination, the concentration of tubocurarine that wasrequired to depress nerve-stimulated force by 50% (Kd,tub) wasdetermined in four experimental conditions: i) control conditions, ii)with CIC-1 inhibitor alone, iii) with neostigmine or pyridostigminealone, and iv) with neostigmine or pyridostigmine and CIC-1 inhibitortogether. FIG. 5A-D show recordings of nerve-stimulated force productionat different tubocurarine concentrations when tested under the fourexperimental conditions. It can be seen that C8 (FIG. 5B) andneostigmine (FIG. 5C) both resulted in elevated nerve-stimulated forcewhen compared to control (FIG. 5A). The force was, however, bestmaintained when both neostigmine and C8 were used (FIG. 5D). To quantifythe effect of compounds on tubocurarine sensitivity, the force at thedifferent tubocurarine concentrations was determined. In plots ofnerve-stimulated force against tubocurarine concentration (FIG. 5E)Kd,tub was determined by fitting four parameter sigmoidal functions tothe data and the Kd,tub for the different compounds have been collectedin Table 4.

TABLE 4 Effect of neostigmine, pyridostigmine, CIC-1 inhibitor, andcombination of neostigmine or pyridostigmine and CIC-1 inhibitor on Kd,tub. Compound Compound (50 μM) + (50 μM) + Neostigmine PyridostigmineCompound Neostigmine Pyridostigmine Compound Control (10 nM) (100 nM)(50 μM) (10 nM) (100 nM) C8 118 ± 5 166 ± 13 177 ± 7 218 ± 18 nM nM*,**nM*,** nM* C8 118 ± 5 127 ± 15 177 ± 7 186 ± 5 nM nM nM*,** nM**Indicates significantly different from control. **Significantlydifferent from the combination of neostigmine and compound.

While the use of tubocurarine mimics conditions with reducedneuromuscular transmission due to post-synaptic dysfunction (myastheniagravis, neuromuscular blockade), the experiments with elevatedextracellular Mg²⁺ mimics conditions with pre-synaptic dysfunction akinto a range of neuromuscular disorders including Lambert Eaton syndrome,motor neuron disorders and polyneuropathy. Patients with Lambert Eatonsyndrome are commonly treated with inhibitors of voltage gated K⁺channels such as 3,4-diaminopyridine (3,4-AP). Based on this it wasdetermined whether recovery of nerve-stimulated force at elevatedextracellular Mg²⁺ with CIC-1 inhibiting compounds could be added toforce recovery with 3,4-AP. This was done by determining theconcentration of Mg²⁺ that was required to depress nerve-stimulatedforce by 50% (Kd,Mg²⁺) in four experimental conditions: i) in controlconditions, ii) with 3,4-AP alone, iii) with C8 alone, and iv) with3,4-AP and C8 together. FIG. 6A-D show recordings of nerve-stimulatedforce production at different Mg²⁺ concentrations when tested underthese four experimental conditions. It can be seen that with both 3,4-APand CIC-1 inhibitor did the nerve-stimulated force at elevated Mg²⁺remain elevated when compared to control. The force was, however, bestmaintained when the combination of both 3,4-AP and CIC-1 inhibitor wasused. To quantify the effect of compounds on Mg²⁺ sensitivity the forceat the different Mg²⁺ concentrations was determined. In plots ofnerve-stimulated force against Mg²⁺ concentration (FIG. 6E) the Kd,Mg²⁺was determined by fitting four parameter sigmoidal function to the data.Kd, Mg²⁺ for the different compounds have been collected in Table 5.

TABLE 5 Effect of 3,4-AP, ClC-1 inhibitor and combination of 3,4-AP andClC-1 inhibitor on Kd, Mg²⁺ Compound (50 μM) + 3,4-AP Compound 3,4-APCompound IUPAC Control (10 μM) (50 μM) (10 μM) C8 (2S)-2-(4-bromo- 3.5 ±0.1 mM 5.8 ± 0.3 mM*,** 4.0 ± 0.1 mM*,** 7.8 ± 0.5 mM* phenoxy)propanoicn = 6 n = 3 n = 7 n = 4 acid *Indicates significantly different fromcontrol. **Significantly different from the combination of 3,4-AP andcompound.

As illustrated in table 5, combination therapy using C8 and3,4-diaminopyridine results in an unexpected synergistic effect onrecovery of neuromuscular transmission.

Example 8: Effect of CIC-1 Inhibitor on Endplate Potentials (EPPs)

Experiments with intracellular electrodes inserted near visible nervesin rat soleus muscles enabled recordings of EPPs upon nerve stimulation.To prevent action potential initiation upon nerve stimulation,p-conotoxin GiiiB (1 μM) was included in the incubation solution toinhibit voltage gated Na⁺ channels in the muscle fibers (NaV1.4). Asshown by representative recordings in FIG. 7A the EPP amplitude becamelarger when C8 was used to inhibit CIC-1 channels. FIG. 7B showsummarized data from all fibers. Both 10 and 25 μM C8 causedsignificantly larger EPPs when compared to control conditions.

Example 9: CIC-1 Inhibition can Recover Contractile Force in HumanMuscles Under Conditions that Mimic Critical Illness Myopathy

Critical illness myopathy (CIM) is a condition that develops in around30% of critically ill patients in intensive care units. The condition isdiagnosed from a loss of muscle excitability as evaluated from reductionin compound muscle action potentials. The associated muscle weaknessprevents patients from weaning from mechanical ventilation and thereforeincreases the stay in intensive care units. At the cellular level, CIMis associated with loss of NaV1.4 function and muscle fibers becomedepolarized. To evaluate whether CIC-1 inhibition can recover musclefunction in such conditions, depolarization and loss of NaV1.4 functionin CIM were mimicked in experiments with isolated human muscles. Fiberswere depolarized by raised extracellular K⁺, and loss of NaV1.4 functionwas induced by a small dose of NaV1.4 inhibitor TTX. As shown by FIG. 8, the contractile force declined upon introducing the elevated K⁺ andTTX. However, contractile force was markedly recovery upon addition ofC8. This confirms that compounds that inhibit CIC-1 such as C8 canprevent loss of force due to depolarization and NaV1.4 loss offunction—the mechanisms underlying CIM.

Example 10: Pharmacokinetic Analysis of C8 in Rats and Effect of CIC-1Inhibition in Animal Models of Myasthenia Gravis

Before conducting in vivo experiments with animal models of myastheniagravis, some pharmacokinetic details were obtained for C8 in response toone-bolus I.P. injection. The details from these experiments have beensummarized in Table 6:

TABLE 6 PK parameters for C8 tested in rats. Parameter Unit Value t½ h3.70 Tmax h 0.5 Cmax ng/ml 44600 C0 ng/ml 24533 AUC 0-t ng/ml*h 203635AUC 0-inf_obs ng/ml*h 205381 AUC 0-t/0-inf_obs 0.9915 VD_obs ml 259.62Cl_obs ml/h 48.69

In the first series of in vivo experiments, myasthenia gravis was simplymimicked by I.P. injection of tubocurarine (0.13 mg/kg) in animals thathad been familiarized to running on the rotarod. On the first of twoconsecutive days, tubocurarine was injected I.P. and the runningperformance of the animal was tested 21 minutes after this injection. Onthe second day of experimentation, the animals first performed a testrun to ensure that they were no longer affected by the tubocurarineinjected the day before. Then C8 (20 mg/kg) or sham treatment wereinjected I.P. and allowed to act for 2 hrs before again injectingtubocurarine. Animals were again tested 21 minutes after this secondtubocurarine treatment. This experimental design enabled a pairedanalysis of whether the sham or C8 injections on the second day changedthe response of the animals to tubocurarine. It should also be notedthat the experimenter did not know which animals had been given C8 orsham treatment. The design of the experiments has been illustrated inFIG. 9A and the results from the experiments are illustrated in FIG.9B-D. As can be seen from FIG. 9B, the animals that were administeredsham-treatment covered almost identical distances on the two days. C8treated animals, however, were able to cover significantly longerdistance on the rotarod on the second day when compared to their ownperformance on the first day. Thus, C8 treated animals ran around 150%longer on the second day (FIG. 9C) clearly contrasting that sham-treatedanimals only ran around 2% longer. To demonstrate that the markedimprovement upon C8 administration was a general response of the animalsand not just a rare observation in a few animals, FIG. 9D shows thenumber of animals in the two groups (sham and C8) that had a performanceincrease of at least 100% on the second day.

In the last series of experiments, myasthenia gravis was mimicked inrats by inducing an immunological reaction against the motor endplate ofmuscle fibers using monoclonal antibody against the nicotinic AChreceptor in muscle fibers. Again the animals had been familiarized tothe rotarod before the MAB35 injection. As shown in FIG. 10 , symptomsof reduced performance developed 21-43 hrs after injection of MAB35.When a stable reduction in performance was observed, the animals wereadministered either C8 or sham. From FIG. 10 it can be seen that uponinjection sham treatment the performance further declined. This declinewas reduced when 20 mg/kg C8 was injected and with the larger dose of C8(30 mg/kg) there was a clear recovery of performance. While there was nodifference in performance between the three groups of animals beforesham or C8 injections, the performance in the groups of animals treatedwith C8 was significantly better than sham-treated animals afterinjection.

Example 11: Electrophysiological Measurement of Compound Inhibition ofCIC-1 in Rat Muscle

The investigatory goal of these experiments was to evaluate whethercompounds inhibit CIC-1 channels in native tissue of rat skeletal musclefibres. Apparent CIC-1 affinity was reported by the concentration ofcompound at which 50% of the compound's full inhibition of CIC-1 wasobserved (EO₅₀).

CIC-1 Cl⁻ ion channels generate around 80% of the total membraneconductance (G_(m)) in resting skeletal muscle fibres of most animalsincluding rat and human. Other ion channels that contribute to G_(m) cantherefore be considered negligible, and it is possible to evaluatewhether a compound inhibits CIC-1 in rat muscle by comparing G_(m)measurements before and after exposure to a compound. CIC-1 inhibitionwould in such recordings be reflected by a reduction of G_(m).

Experimentally, G_(m) was measured in individual fibres of whole ratsoleus muscles using a three micro-electrodes technique described inthis example and in full detail elsewhere. Briefly, intact rat soleusmuscles were dissected out from 12-14 week old Wistar rats and placed inan experimental chamber that was perfused with a standard Krebs Ringersolution containing 122 mM NaCl, 25 mM NaHCO₃, 2.8 mM KCl, 1.2 mMKH₂PO₄, 1.2 mM MgSO₄, 1.3 mM CaCl₂, 5.0 mM D-glucose. Duringexperiments, the solution was kept at approx. 30° C. and continuouslyequilibrated with a mixture of 95% 02 and 5% CO₂, pH˜7.4. Theexperimental chamber was placed in Nikon upright microscope that wasused to visualize individual muscle fibres and the three electrodes(glass pipettes filled with 2 M potassium citrate). For G_(m)measurements, the electrodes were inserted into the same fibre withknown inter-electrode distances of 0.35-0.5 mm (V1-V2, X1) and 1.1-1.5mm (V1-V3, X3) (FIG. 1A). The membrane potential of the impaled musclefibre was recorded by all electrodes. Two of the electrodes werefurthermore used to inject 50 ms current pulses of −30 nA. Given thepositions of the electrodes, three different inter-electrode distancescould be identified (X1-X2, X1-X3, X2-X3) and hence the membranepotential responses to the current injections could be obtained at threedistances from the point of current injection. The steady state voltagedeflection at each distance was divided by the magnitude of currentinjected (−30 nA) and the resulting transfer resistances were plottedagainst inter-electrode distance and the data was fitted to amono-exponential function from which G_(m) could be calculated usinglinear cable theory (FIG. 1B).

To establish a dose response relationship, G_(m) was first determined in10 muscle fibres in the absence of compound and then at four increasingcompound concentrations with G_(m) determinations in 5-10 fibres at eachconcentration. The average G_(m) values at each concentration wereplotted against compound concentration and the data was fitted tosigmoidal function to obtain an EO₅₀ value (FIG. 10 ). Table 7 shows theEC₅₀ values for a range of compounds with n values referring to numberof experiments that each reflect recordings from around 50 fibres.

TABLE 7 Inhibition of ClC-1 ion channel using compounds of the inventionCompound investigated EC₅₀ (μM) Compound A-6 7.4 ± 1.4 (n = 4) CompoundA-26 3.8 ± 0.8 (n = 7) Compound A-27 4.5 ± 1.7 (n = 7) Compound(2R)-A-27 >80 (n = 1) Compound A-31 7.2 ± 2.8 (n = 2) Compound A-40 4.2± 0.6 (n = 3) Compound A-54 6.8 ± 1.3 (n = 2) Compound A-58 6.3 ± 2.4 (n= 2) Compound A-60 7.5 ± 1.0 (n = 3) Compound A-66 7.2 (n = 1) CompoundA-67 9.4 ± 0.6 (n = 2) Compound A-71 10.1 ± 0.2 (n = 2) Compound A-737.2 (n = 1) Compound A-74 4.0 ± 0.1 (n = 2) Compound A-76 3.8 ± 2.1 (n =3) Compound A-78 7.6 ± 1.6 (n = 3) Compound A-82 5.2 ± 1.3 (n = 4)Compound A-83 8.0 (n = 1) Compound A-85 10.0 ± 9.5 (n = 4) Compound A-868.9 ± 3.2 (n = 3) Compound A-87 4.5 ± 0.8 (n = 3) Compound A-88 5.9 ±1.6 (n = 3) Compound A-89 8.7 ± 1.4 (n = 2) Compound A-90 2.3 (n = 1)Compound A-94 12.0 ± 3.2 (n = 3) Compound A-95 12.5 ± 1.4 (n = 4)

In conclusion, this example demonstrates that the compounds of thepresent invention have an EC₅₀ value in the range of 3-10 μM. Forexample, compound A-27 has an EC₅₀ value of 4.5 μM. In comparison, the(2R)-enantiomer of compound A-27 has an EC₅₀ value higher than 80 μM,which demonstrates that the chiral centre significantly influences theactivity on the CIC-1 channel.

Example 12: Measurement of Force in an In Vitro Model

The current invention relates to compounds that inhibit CIC-1 ionchannels and increase muscle excitability and thereby improve musclefunction in clinical conditions where muscle activation is failing. Suchconditions result in loss of contractile function of skeletal muscle,weakness and excessive fatigue. In this series of experiments thecompounds were tested for their ability to restore contractile functionof isolated rat muscle when the neuromuscular transmission had beencompromised akin to neuromuscular disorders.

Experimentally, soleus muscles from 4-5 wk old rats were isolated withthe motor nerve remaining attached. The nerve-muscle preparations weremounted in experimental setups that enabled electrical stimulation ofthe motor nerve. Stimulation of the motor nerve led to activation of themuscle fibres and ensuing force production that was recorded. Thenerve-muscle preparations were also in these experiments incubated inthe standard Krebs Ringer (see example 5) and the solution was heated to30° C. and continuously equilibrated with a mixture of 95% O₂ and 5%CO₂, pH˜7.4.

After mounting the nerve-muscle preparation in the experimental setup,the contractile function of the muscle was initially assessed under thecontrol conditions (FIG. 2A). Sub-maximal concentration of tubocurarine(115 nM), an acetylcholine receptors antagonist, was then added to theexperimental bath to impose partial inhibition of the ability of themotor nerve to activate the muscle fibres. The experimental conditionmimics the failing neuromuscular transmission in a range ofneuromuscular disorders. After addition of tubocurarine the contractileforce declined over the next 90 mins to 10-50% of the control force. 50μM of the test compound was then added and the contractile forcerecovered despite the continued presence of tubocurarine. To quantifythe ability of the compound to restore force the percentage of theinitial force that was restored was determined after 40 mins of compoundexposure (FIG. 2B) and the point increase is reported in Table 8.

TABLE 8 Percentage increase of initial force that was restored Compoundinvestigated Point increase (%) Compound A-6 44 Compound A-26 39Compound (2R)-A-26 −6 Compound A-27 46 Compound A-31 42 Compound(2R)-A-31 −8 Compound A-40 20 Compound A-58 44 Compound A-60 62 Compound(2R)-A-60 −2 Compound A-66 51 Compound A-67 40 Compound A-71 49 CompoundA-73 51 Compound A-74 42 Compound A-76 62 Compound A-78 38 Compound A-8248 Compound (2R)-A-82 −4 Compound A-83 35 Compound A-85 37 Compound A-8645 Compound A-87 37 Compound A-88 55 Compound A-89 33 Compound A-90 57Compound A-94 31 Compound (2R,3R)-A-94 −4 Compound A-95 39 Compound(2R,3R)-A-95 −7

In conclusion, this example demonstrates that the compounds of thepresent invention are able to increase muscle excitability and therebyimprove muscle function in clinical conditions. The muscle contractilitywas recovered by 20-46% points, which meant almost complete restorationof the force.

The data further demonstrates that neither the (2R)-enantiomers areunable to recover force compared to the enantiomerically pure(2S)-enantiomers.

Example 13: Screening of Compounds on the Human Isoform of CIC-1Expressed in CHO Cells Using Automated Patch-Clamp

The investigatory goal of these experiments was to evaluate howcompounds affect the open probability and current amplitude of humanCIC-1 channels expressed in CHO cells. Experiments were performed usingan automated patch clamp system that allowed high throughput testing ofwhole cell patches together with both intracellular and extracellularaddition of compound.

Automated Voltage Clamp Measurements

Automated whole cell patch clamp experiments were performed with theQpatch 16 system (Sophion Bioscience, Ballerup, Denmark) at roomtemperature. Data acquisition and analysis were performed in the Qassaysoftware (ver. 5.6, Odense).

Voltage Protocol and Analysis of Whole Cell CIC-1 Currents

To evoke CIC-1 currents in whole cell patches, the membrane potentialwas initially stepped from a holding potential of −30 mV to +60 mV for100 ms and then to various test voltages (sweeps) ranging from +120 mVto −140 mV in steps of 20 mV for 300 ms. To obtain tail currents, themembrane potential was stepped to −100 mV after each test voltage for300 ms and then relaxed to −30 mV for 2 sec between sweeps (FIG. 3 ).I/V relationships for whole cell instant and steady state currentamplitudes were obtained by plotting average current densities at thebeginning and at the end of the 300 ms step against the membranepotential (FIG. 4 ).

In order to determine the relative overall open probability (Po), theinstantaneous tail currents were normalized to the maximal tail currentobtained following the most positive voltage step and plotted againstthe test voltage. Plots of normalized tail currents from each whole cellpatch were then fitted to a Boltzmann function allowing determination ofhalf activation voltages (V_(1/2), FIG. 5 ).

Solutions

For automated patch clamp experiments extracellular solutions contained:2 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, 4 mM KCl, 145 mM NaCl, 10 mMGlucose, pH adjusted to 7.4 with NaOH (2 M). Osmolality adjusted to ˜320using sucrose.

Intracellular solutions contained: 80 mM C₅ F, 60 mM CsCl, 5/1 mMKOH/EGTA, 10 mM HEPES, 10 mM NaCl, pH adjusted to 7.2 with NaOH (2 M).Osmolality adjusted to ˜320 mOsm using sucrose.

Cell Line Information:

Cells used in patch clamp experiments were Chinese hamster ovary cells(CHO) constitutively expressing human CIC-1 channels. The amino acidsequence encoded by the cDNA used to create this cell line was identicalto the translated sequence for GenBank accession number NM_000083.2.Cells were produced by Charles River (Catalogue CT6175, Cleveland Ohio,USA) in a cryopreserved format. Experiments were performed on the cellsdirectly after thawing (3×10⁶ cells used in each experiment).

Test Protocol

To evaluate the compound effect on CIC-1, when applied directly to theintracellular side of the cell membrane, the half activation voltage,V_(1/2), was determined from whole cell patches with compound added tothe intracellular solution and then compared to V_(1/2) determined fromcontrol cell patches with only vehicle added to the intracellularsolution. Additionally, the effect of extracellular added compound wasevaluated by determine V_(1/2) and steady state current amplitudesbefore and after exchanging the extracellular solution to containcompound.

The difference in half activation voltage of CIC-1 channels, □V_(1/2),was determined as the difference between the cell patches treatedintracellularly with compound and control cells patches and is reportedin Table 4 below. A positive shift in □V_(1/2) is reflecting CIC-1channel inhibition by the tested compound. P-values of <0.05 isconsidered significant.

TABLE 4 Percentage increase of initial force that was restored Compoundinvestigated ΔV½ (mV) P-value Compound A-6 13.0 <0.01 Compound A-8 9.4<0.01 Compound A-9 15.2 <0.01 Compound A-26 19.7 <0.01 Compound A-2720.2 <0.01 Compound A-38 17.4 <0.01 Compound A-40 5.19 <0.01 CompoundA-58 28.2 <0.01 Compound A-60 20.0 <0.01 Compound A-66 27.4 <0.01Compound A-67 37.8 <0.01 Compound A-69 32.6 <0.01 Compound A-74 10.4<0.01 Compound A-76 26.2 <0.01 Compound A-82 19.0 <0.01 Compound A-8512.5 <0.01 Compound A-87 16.4 <0.01 Compound A-89 10.3 <0.01 CompoundA-95 10.3 <0.01

Example 14: Measurement of In Situ Muscle Contractile Characteristics

Isometric hindlimb force was measured in 12-week old female Lewis ratsin the presence and absence of compound.

Rats were placed under anesthesia with isoflurane (2-4%), intubated andsubsequently connected to a micro ventilator (Microvent 1, HallowellEMC, US). Two stimulation electrodes were inserted through the skin tostimulate the sciatic nerve. A small incision was made proximal to theankle, to expose the Achilles tendon, which was tied by cotton string,and connected to a force transducer (Fort250, World PrecisionInstruments) with adjustable position (Vernier control). The Achillestendon was then cut distal to the attached cotton string. The rat wasplaced on a heated pad, and to prevent movement artefacts fromcontraction of the ankle dorsiflexors, the foot was fixated by tape on afootplate.

Muscle contractile properties were assessed by applying an electricalcurrent (under supramaximal voltage conditions) to the nerve andrecording the force generated by the muscle. The muscle was stretcheduntil maximal force was obtained, when assessed by 2 Hz stimulation.Isometric force was measured every 30 seconds at 12 Hz (Twitch), 10pulses, and at every 5 minutes at 80 Hz (Tetanic) for 1 second (80pulses). This stimulation pattern was employed throughout theexperiment, expect in few cases where 80 Hz stimulation was replaced by12 Hz (10 pulses). Neuromuscular transmission was partially inhibited byconstant infusion of Cisatracurium (Nimbex, GlaxoSmithKline) at aconcentration of 0.1 mg/kg at an adjustable infusion speed, adjustedindividually for each animal to obtain a level of inhibition of ca. 50%of the forced generated at 12 Hz stimulation on the 4th pulse. When thelevel of neuromuscular inhibition was stable, the test article wasinjected i.v. at the chosen concentration. The effect of test articlewas assessed on its ability to increase force generated from thestimulation pattern applied. The effect was assessed in the ability toincrease force per se (tetanic, 80 Hz, stimulation), and the ratiobetween individual twitch peaks (12 Hz stimulation). The effect wasmonitored for at least 1 hour after injection of test article. Inaddition, the time from injection of test article to maximal effect onforce (both twitch and tetanic) was noted and the time for the effect todisappear (return to baseline), if possible. When appropriate theinfusion of neuromuscular blocking agent was ceased, with thestimulation pattern continued, and the return of force to control levelswas monitored. Animals were sacrificed by cervical dislocation whilestill fully sedated.

Compound A-27 was dosed 40 mg/kg i.v. The average increase in tetanicforce was 36.4% and the average increase in twitch peaks was 12.2% (3experiments).

Compound A-31 was dosed 20 mg/kg i.v. The average increase in tetanicforce was 29.8% and the average increase in twitch peaks was 7.3% (3experiments).

Compound A-60 was dosed 20 mg/kg i.v. The average increase in tetanicforce was 52.7% and the average increase in twitch peaks was 18.5% (3experiments).

Compound A-87 was dosed 42 mg/kg i.v. The average increase in tetanicforce was 19.3% and the average increase in twitch peaks was 5.8% (2experiments).

Compound A-94 was dosed 21 mg/kg i.v. The average increase in tetanicforce was 34.8% and the average increase in twitch peaks was 11.5% (2experiments).

This demonstrates that compounds of the invention, such as CompoundsA-27, A-31, A-60, A-87 and A-94 can restore force to muscles in vivowhich have been partially inhibited by a neuromuscular blocker.

The invention claimed is:
 1. A compound of Formula (Ha):

wherein: R¹ is selected from the group consisting of F, Cl, Br, I, —CN,—CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and —S—CH₃;R² is independently selected from the group consisting of hydrogen,deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime optionally substitutedwith C₁ alkyl; R³ is selected from the group consisting of C₂₋₅ alkynyl,and C₄₋₅ cycloalkyl, each of which may be optionally substituted withone or more, identical or different, substituents R⁵; R⁴ is selectedfrom the group consisting of H, C₁₋₅ alkyl optionally substituted withone or more, identical or different, substituents R⁷, C₃₋₆ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷, phenyl optionally substituted with one or more,identical or different, substituents R⁸ and benzyl optionallysubstituted with one or more, identical or different, substituents R⁸;R⁵ is independently selected from the group consisting of deuterium, F,OC₁₋₅ alkyl optionally substituted with one or more, identical ordifferent, substituents R⁷, OC₃₋₅ cycloalkyl optionally substituted withone or more, identical or different, substituents R⁷, and OH; R⁶ isindependently selected from the group consisting of hydrogen anddeuterium; R⁷ is independently selected from the group consisting ofdeuterium and F; R⁸ is independently selected from the group consistingof deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and n is aninteger 0, 1, 2, 3 or 4; or a pharmaceutically acceptable salt, hydrate,polymorph, tautomer, or solvate thereof.
 2. The compound according toclaim 1, wherein the compound is a compound of Formula (VII.2):

wherein: R¹ is selected from the group consisting of F, Cl, Br, I, —CN,—CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and —S—CH₃;R² is independently selected from the group consisting of hydrogen,deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime optionally substitutedwith C₁ alkyl; R³ is selected from the group consisting of C₂₋₅ alkynyl,and C₄₋₅ cycloalkyl, each of which may be optionally substituted withone or more, identical or different, substituents R⁵; R⁴ is selectedfrom the group consisting of H, C₁₋₅ alkyl optionally substituted withone or more, identical or different, substituents R⁷, C₃₋₆ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷, phenyl optionally substituted with one or more,identical or different, substituents R⁸ and benzyl optionallysubstituted with one or more, identical or different, substituents R⁸;R⁵ is independently selected from the group consisting of deuterium, F,OC₁₋₅ alkyl optionally substituted with one or more, identical ordifferent, substituents R⁷, OC₃₋₅ cycloalkyl optionally substituted withone or more, identical or different, substituents R⁷, and OH; R⁶ isindependently selected from the group consisting of hydrogen anddeuterium; R⁷ is independently selected from the group consisting ofdeuterium and F; R⁸ is independently selected from the group consistingof deuterium, methoxy, nitro, cyano, Cl, Br, I and F; R⁹ is deuterium;and n is an integer 0, 1, 2, or 3; or a pharmaceutically acceptablesalt, hydrate, polymorph, tautomer, or solvate thereof.
 3. The compoundaccording to claim 2, wherein: R¹ is selected from the group consistingof Cl and Br; R² is selected from the group consisting of F, Cl and Br;R³ is selected from the group consisting of C₂₋₅ alkynyl, and C₄₋₅cycloalkyl, each of which may be optionally substituted with one ormore, identical or different, substituents R⁵; R⁴ is selected from thegroup consisting of H, C₁₋₅ alkyl optionally substituted with one ormore, identical or different, substituents R⁷, C₃₋₆ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷ and phenyl optionally substituted with one or more,identical or different, substituents R⁸; R⁵ is independently selectedfrom the group consisting of deuterium, F, —OC₁₋₅ alkyl optionallysubstituted with one or more, identical or different, substituents R⁷and —OC₃₋₅ cycloalkyl optionally substituted with one or more, identicalor different, substituents R⁷; R⁶ is selected from the group consistingof hydrogen and deuterium; R⁷ is independently selected from the groupconsisting of deuterium and F; R⁸ is independently selected from thegroup consisting of deuterium, methoxy, nitro, cyano, Cl, Br, I and F;R⁹ is deuterium; and n is 0, 1, 2 or 3 or a pharmaceutically acceptablesalt, hydrate, polymorph, tautomer, or solvate thereof.
 4. The compoundaccording to claim 2, wherein: R¹ is Br; R² is selected from the groupconsisting of F, Cl and Br; R³ is C₄ cycloalkyl optionally substitutedwith one or more, identical or different, substituents R⁵; R⁴ is H; R⁵is independently selected from the group consisting of deuterium, F,—OC₁₋₅ alkyl optionally substituted with one or more, identical ordifferent, substituents R⁷ and —OC₃₋₅ cycloalkyl optionally substitutedwith one or more, identical or different, substituents R⁷; R⁶ isselected from the group consisting of hydrogen and deuterium; R⁷ isindependently selected from the group consisting of deuterium and F; R⁹is deuterium; and n is 0, 1, 2 or 3 or a pharmaceutically acceptablesalt, hydrate, polymorph, tautomer, or solvate thereof.
 5. The compoundaccording to claim 2, wherein: R¹ is selected from the group consistingof F, Cl, Br, I; R² is selected from the group consisting of hydrogen,deuterium, F, Cl, Br, I; R³ is selected from the group consisting ofC₂₋₅ alkynyl, and C₄₋₅ cycloalkyl, each of which is substituted with oneor more, identical or different, substituents R⁵; and R⁴ is selectedfrom the group consisting of H, C₁₋₅ alkyl optionally substituted withone or more, identical or different, substituents R⁷, C₃₋₆ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷, phenyl optionally substituted with one or more,identical or different, substituents R⁸ and benzyl optionallysubstituted with one or more, identical or different, substituents R⁸;R⁵ is independently selected from the group consisting of deuterium, F,OC₁₋₅ alkyl optionally substituted with one or more, identical ordifferent, substituents R⁷ and OC₃₋₅ cycloalkyl optionally substitutedwith one or more, identical or different, substituents R⁷; R⁶ isselected from the group consisting of hydrogen and deuterium; R⁷ isindependently selected from the group consisting of deuterium and F; andR⁸ is independently selected from the group consisting of deuterium,methoxy, nitro, cyano, Cl, Br, I and F; R⁹ is deuterium; and n is 0, 1,2 or 3; or a pharmaceutically acceptable salt, hydrate, polymorph,tautomer, or solvate thereof.
 6. The compound according to claim 1,wherein: R¹ is Br; R² is selected from the group consisting of hydrogen,deuterium, F, Cl and Br; R³ is C₂₋₅ alkynyl substituted with one ormore, identical or different, substituents R⁵; R⁴ is H; R⁵ isindependently selected from the group consisting of deuterium, F, —OC₁₋₅alkyl optionally substituted with one or more, identical or different,substituents R⁷ and —OC₃₋₅ cycloalkyl optionally substituted with one ormore, identical or different, substituents R⁷; R⁶ is selected from thegroup consisting of hydrogen and deuterium; R⁷ is independently selectedfrom the group consisting of deuterium and F; and n is 0, 1, 2, 3, or 4;or a pharmaceutically acceptable salt, hydrate, polymorph, tautomer, orsolvate thereof.
 7. The compound according to claim 1, wherein thecompound is selected from the group consisting of:(2S)-2-(4-bromophenoxy)pent-4-ynoic acid;(2S)-2-(4-bromophenoxy)-3-cyclopropylpropanoic acid;(2S)-2-(2,4-dibromophenoxy)pent-4-ynoic acid;(2S)-2-(4-bromo-2-chlorophenoxy)pent-4-ynoic acid;(2S)-2-(4-bromo-2-fluorophenoxy)pent-4-ynoic acid;(2S)-2-(4-bromo-2-chlorophenoxy)-2-cyclobutylacetic acid;(2S)-2-(4-bromo-2-chlorophenoxy)-3-cyclopropylpropanoic acid;(2S)-2-(4-bromophenoxy)-2-cyclobutylacetic acid; and(2S)-2-(4-bromo-2-fluorophenoxy)-2-cyclobutylacetic acid.
 8. A method ofinhibiting a CIC-1 receptor in a patient, comprising administering to apatient in need thereof a compound of Formula (IIa) according to claim1:

wherein: R¹ is selected from the group consisting of F, Cl, Br, I, —CN,—CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and —S—CH₃;R² is independently selected from the group consisting of hydrogen,deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime optionally substitutedwith C₁ alkyl; R³ is selected from the group consisting of C₂₋₅ alkynyl,and C₄₋₅ cycloalkyl, each of which may be optionally substituted withone or more, identical or different, substituents R⁵; R⁴ is selectedfrom the group consisting of H, C₁₋₅ alkyl optionally substituted withone or more, identical or different, substituents R⁷, C₃₋₆ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷, phenyl optionally substituted with one or more,identical or different, substituents R⁸ and benzyl optionallysubstituted with one or more, identical or different, substituents R⁸;R⁵ is independently selected from the group consisting of deuterium, F,OC₁₋₅ alkyl optionally substituted with one or more, identical ordifferent, substituents R⁷, OC₃₋₅ cycloalkyl optionally substituted withone or more, identical or different, substituents R⁷, and OH; R⁶ isindependently selected from the group consisting of hydrogen anddeuterium; R⁷ is independently selected from the group consisting ofdeuterium and F; R⁸ is independently selected from the group consistingof deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and n is aninteger 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, hydrate,polymorph, tautomer, or solvate thereof.
 9. A method of treating, and/orameliorating a neuromuscular disorder in a subject or reversing and/orameliorating a neuromuscular blockade in a subject, comprisingadministering to a subject in need thereof a compound according to claim1 of Formula (IIa):

wherein: R¹ is selected from the group consisting of F, Cl, Br, I, —CN,—CF₃, C₁₋₄ alkyl, C₂₋₄ alkenyl, C₂₋₄ alkynyl, C₄ cycloalkyl and —S—CH₃;R² is independently selected from the group consisting of hydrogen,deuterium, F, Cl, Br, I, —CN, —CF₃ and -oxime optionally substitutedwith C₁ alkyl; R³ is selected from the group consisting of C₂₋₅ alkynyl,and C₄₋₅ cycloalkyl, each of which may be optionally substituted withone or more, identical or different, substituents R⁵; R⁴ is selectedfrom the group consisting of H, C₁₋₅ alkyl optionally substituted withone or more, identical or different, substituents R⁷, C₃₋₆ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷, phenyl optionally substituted with one or more,identical or different, substituents R⁸ and benzyl optionallysubstituted with one or more, identical or different, substituents R⁸;R⁵ is independently selected from the group consisting of deuterium, F,OC₁₋₅ alkyl optionally substituted with one or more, identical ordifferent, substituents R⁷, OC₃₋₅ cycloalkyl optionally substituted withone or more, identical or different, substituents R⁷, and OH; R⁶ isindependently selected from the group consisting of hydrogen anddeuterium; R⁷ is independently selected from the group consisting ofdeuterium and F; R⁸ is independently selected from the group consistingof deuterium, methoxy, nitro, cyano, Cl, Br, I and F; and n is aninteger 0, 1, 2, 3 or 4, or a pharmaceutically acceptable salt, hydrate,polymorph, tautomer, or solvate thereof.
 10. The method according toclaim 9, wherein the neuromuscular disorder is selected from the groupconsisting of myasthenia gravis (such as autoimmune and congenitalmyasthenia gravis), Lambert-Eaton Syndrome, critical illness myopathy,amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA),critical illness myopathy (CIM), reversal diabetic polyneuropathy,Guillain-Barré syndrome, poliomyelitis, post-polio syndrome, chronicfatigue syndrome, critical illness polyneuropathy, and hyperkalemicperiodic paralysis.
 11. The method according to claim 9, wherein theneuromuscular disorder is amyotrophic lateral sclerosis (ALS).
 12. Themethod according to claim 9, wherein the neuromuscular disorder ismyasthenia gravis.
 13. The method according to claim 9, wherein theneuromuscular disorder has been induced by a neuromuscular blockingagent.
 14. The compound according to claim 1, wherein: R¹ is Br; R² isselected from the group consisting of F, Cl and Br; R³ is C₄ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁵; R⁴ is H; R⁵ is independently selected from the groupconsisting of deuterium, F, —OC₁₋₅ alkyl optionally substituted with oneor more, identical or different, substituents R⁷ and —OC₃₋₅ cycloalkyloptionally substituted with one or more, identical or different,substituents R⁷; R⁶ is selected from the group consisting of hydrogenand deuterium; R⁷ is independently selected from the group consisting ofdeuterium and F; and n is 0, 1, 2 or 3; or a pharmaceutically acceptablesalt, hydrate, polymorph, tautomer, or solvate thereof.
 15. The compoundaccording to claim 2, wherein: R¹ is Br; R² is selected from the groupconsisting of hydrogen, deuterium, F, Cl and Br; R³ is C₂₋₅ alkynylsubstituted with one or more, identical or different, substituents R⁵;R⁴ is H; R⁵ is independently selected from the group consisting ofdeuterium, F, —OC₁₋₅ alkyl optionally substituted with one or more,identical or different, substituents R⁷ and —OC₃₋₅ cycloalkyl optionallysubstituted with one or more, identical or different, substituents R⁷;R⁶ is selected from the group consisting of hydrogen and deuterium; R⁷is independently selected from the group consisting of deuterium and F;R⁹ is deuterium; and n is 0, 1, 2, or 3; or a pharmaceuticallyacceptable salt, hydrate, polymorph, tautomer, or solvate thereof. 16.The compound of claim 1 wherein R³ is C₄₋₅ cycloalkyl that is selectedfrom the group consisting of cyclobutyl, cyclopropylmethyl, andcyclopentyl.
 17. The compound of claim 4 wherein R³ is C₄ cycloalkylthat is selected from the group consisting of cyclobutyl andcyclopropylmethyl.
 18. The compound of claim 14 wherein R³ is C₄cycloalkyl that is selected from the group consisting of cyclobutyl andcyclopropylmethyl.
 19. The compound of claim 1 wherein R³ is C₂₋₅alkynyl that is selected from the group consisting of ethynyl, propynyl,butynyl and pentynyl.
 20. The compound of claim 15 wherein R³ is C₂₋₅alkynyl that is selected from the group consisting of ethynyl, propynyl,butynyl and pentynyl.